1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS

ABSTRACT

The present invention relates to novel triazolo[4,3-a]pyridine derivatives of Formula (I) 
     
       
         
         
             
             
         
       
     
     wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

FIELD OF THE INVENTION

The present invention relates to novel triazolo[4,3-a]pyridinederivatives which are positive allosteric modulators of the metabotropicglutamate receptor subtype 2 (“mGluR2”) and which are useful for thetreatment or prevention of neurological and psychiatric disordersassociated with glutamate dysfunction and diseases in which the mGluR2subtype of metabotropic receptors is involved. The invention is alsodirected to pharmaceutical compositions comprising such compounds, toprocesses to prepare such compounds and compositions, and to the use ofsuch compounds for the prevention or treatment of neurological andpsychiatric disorders and diseases in which mGluR2 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system. Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function.

Furthermore, glutamate is at the centre of several differentneurological and psychiatric diseases, where there is an imbalance inglutamatergic neurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), and the NMDA, AMPA andkainate receptors which are responsible for fast excitatorytransmission.

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor which results in the activation of the G-protein andintracellular signalling pathways.

The mGluR2 subtype is negatively coupled to adenylate cyclase viaactivation of Gαi-protein, and its activation leads to inhibition ofglutamate release in the synapse. In the central nervous system (CNS),mGluR2 receptors are abundant mainly throughout cortex, thalamicregions, accessory olfactory bulb, hippocampus, amygdala,caudate-putamen and nucleus accumbens.

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders. In addition, activating mGluR2 in variousanimal models was shown to be efficacious, thus representing a potentialnovel therapeutic approach for the treatment of schizophrenia, epilepsy,drug addiction/dependence, Parkinson's disease, pain, sleep disordersand Huntington's disease.

To date, most of the available pharmacological tools targeting mGluRsare orthosteric ligands which activate several members of the family asthey are structural analogues of glutamate.

A new avenue for developing selective compounds acting at mGluRs is toidentify compounds that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. Variouscompounds have been described as mGluR2 positive allosteric modulators.WO 2009/062676 (Ortho-McNeil-Janssen Pharmaceuticals, Inc. and AddexPharma S.A.) published on 22 May 2009 discloses imidazo[1,2-a]pyridinederivatives as mGluR2 positive allosteric modulators. WO2010/130424,WO2010/130423 and WO2010/130422, published on 18 Nov. 2010, disclose1,2,4-triazolo[4,3-a]pyridine derivatives as mGluR2 positive allostericmodulators.

It was demonstrated that such compounds do not activate the receptor bythemselves. Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate, which by itself induces aminimal response. Mutational analysis has demonstrated unequivocallythat the binding of mGluR2 positive allosteric modulators does not occurat the orthosteric site, but instead at an allosteric site situatedwithin the seven transmembrane region of the receptor.

Animal data suggest that positive allosteric modulators of mGluR2 haveeffects in anxiety and psychosis models similar to those obtained withorthosteric agonists. Allosteric modulators of mGluR2 were shown to beactive in fear-potentiated startle, and in stress-induced hyperthermiamodels of anxiety. Furthermore, such compounds were shown to be activein reversal of ketamine- or amphetamine-induced hyperlocomotion, and inreversal of amphetamine-induced disruption of prepulse inhibition of theacoustic startle effect models of schizophrenia.

Recent animal studies further reveal that the selective positiveallosteric modulator of metabotropic glutamate receptor subtype 2biphenyl-indanone (BINA) blocks a hallucinogenic drug model ofpsychosis, supporting the strategy of targeting mGluR2 receptors fortreating glutamatergic dysfunction in schizophrenia.

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 or DCG-IV. These dataprovide evidence for yet another novel therapeutic approach to treat theabove mentioned neurological and psychiatric diseases involving mGluR2,which would use a combination of a positive allosteric modulator ofmGluR2 together with an orthosteric agonist of mGluR2.

DESCRIPTION OF THE INVENTION

The present invention is directed to potent mGluR2 PAM compounds with anadvantageous balance of properties. In particular, the compoundsaccording to the present invention show appropriate potency and/ormetabolic balance and brain occupancy after oral dosing.

Accordingly, the present invention is directed to a compound accordingto Formula (I)

or a stereochemically isomeric form thereof,whereinR¹ is selected from the group consisting of C₁₋₆alkyl;(C₃₋₈cycloalkyl)C₁₋₃alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl; and C₁₋₃alkylsubstituted with 1, 2 or 3 fluoro substituents;R² is selected from the group consisting of C₁, CF₃, —CN andcyclopropyl;R³ is selected from the group consisting of hydrogen, methyl and CF₃;R⁴ is selected from the group consisting of hydrogen and methyl;or R³ and R⁴ together with the carbon to which they are bound form acyclopropyl ring;L is selected from the group consisting of (L-a), (L-b), (L-c), (L-d),(L-e), (L-f), (L-g) and (L-h):

whereinm^(a), M^(b), and m^(c) are each independently selected from the groupconsisting of 0 and 1; m^(e) and m^(g) are each independently selectedfrom the group consisting of 1 and 2;n^(a), n^(b), n^(c), n^(d), n^(e), n^(f), h^(g) and n^(h) are eachindependently selected from the group consisting of 0, 1 and 2;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g) and R^(5h) areeach independently selected from the group consisting of halo; C₁₋₃alkyl; C₁₋₃ alkyl substituted with 1, 2 or 3 fluoro substituents;C₁₋₃alkyloxy; and C₁₋₃alkyloxy substituted with 1, 2 or 3 fluorosubstituents. R^(6a) is selected from the group consisting of hydrogen;halo; C₁₋₃alkyl; C₁₋₃alkyl substituted with 1, 2 or 3 fluorosubstituents; C₁₋₃alkyloxy; and C₁₋₃alkyloxy substituted with 1, 2 or 3fluoro substituents;R^(6c) is selected from the group consisting of hydrogen; halo;C₁₋₃alkyl; C₁₋₃alkyl substituted with 1, 2 or 3 fluoro substituents;C₁₋₃alkyloxy; C₁₋₃alkyloxy substituted with 1, 2 or 3 fluorosubstituents; and cyclopropyl;R^(7a), R^(8a), R^(7b) and R^(8b) are each independently selected fromthe group consisting of hydrogen; fluoro and methyl; or R^(7a) andR^(8a), and R^(7b) and R^(8b) together with the carbon to which they areattached form a cyclopropyl or a carbonyl group;whereineach halo is selected from the group consisting of fluoro, chloro, bromoand iodo;with the proviso that (L-c) is not bound to the triazolopyridine corethrough a carbon atom that is alpha to the oxygen atom;or a pharmaceutically acceptable salt or a solvate thereof.

The present invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) and a pharmaceutically acceptable carrier or excipient.

Additionally, the invention relates to a compound of Formula (I) for useas a medicament and to a compound of Formula (I) for use as a medicamentfor the treatment or prevention of neurological and psychiatricdisorders in which mGluR2 is involved.

The invention also relates to the use of a compound according to Formula(I) or a pharmaceutical composition according to the invention for themanufacture of a medicament for treating or preventing neurological andpsychiatric disorders in which mGluR2 is involved.

Additionally, the invention relates to the use of a compound of Formula(I) in combination with an additional pharmaceutical agent for themanufacture of a medicament for treating or preventing neurological andpsychiatric disorders in which mGluR2 is involved.

Furthermore, the invention relates to a process for preparing apharmaceutical composition according to the invention, characterized inthat a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound of Formula (I).

The invention also relates to a product comprising a compound of Formula(I) and an additional pharmaceutical agent, as a combined preparationfor simultaneous, separate or sequential use in the treatment orprevention of neurological or psychiatric disorders and diseases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of Formula (I) as definedhereinbefore, stereochemically isomeric forms thereof andpharmaceutically acceptable salts and solvates thereof. The compounds offormula (I) have mGluR2 modulator activity, and are useful in thetreatment or prophylaxis of neurological and psychiatric disorders.

In an embodiment, the invention relates to a compound of formula (I) aspreviously defined, wherein R¹ is selected from the group consisting of(cyclopropyl)methyl; ethyl; and (ethoxy)methyl.In an additional embodiment, R¹ is (C₃₋₈cycloalkyl)C₁₋₃alkyl.In an additional embodiment, R¹ is (cyclopropyl)methyl.In an additional embodiment, R² is CF₃ or Cl.In an additional embodiment, R³ and R⁴ are both hydrogen.In an additional embodiment L is

wherein R^(5a) is fluoro and n^(a) is selected from the group consistingof 0, 1 and 2.In an additional embodiment L is

wherein R^(5b) is fluoro and n^(b) is selected from the group consistingof 0, 1 and 2.In an additional embodiment L is selected from (L-c1), (L-c2), (L-c3)and (L-c4)

wherein each R^(6c) is independently selected from hydrogen and methyl.In an additional embodiment L is (L-d), wherein n^(d) is 0.In an additional embodiment L is selected from (L-e1), (L-e2) and (L-f1)

wherein m^(e) is selected from the group consisting of 1 and 2.In an additional embodiment L is (L-g1)

wherein mg is selected from 1 and 2.In an additional embodiment L is (L-d1)

In an additional embodiment L is (L-h1)

In an additional embodiment L is selected from the group selected from(L-a1), (L-b1), (L-c1), (L-c2), (L-c3), (L-c4), (L-e1), (L-e2), (L-f1),(L-g1) and (L-d) wherein n^(d) is 0.

All possible combinations of the above-indicated interesting embodimentsare considered to be embraced within the scope of this invention.

Particular compounds may be selected from the group of

-   3-(cyclopropylmethyl)-N-[trans-4-(2,4-difluorophenyl)cyclohexyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-(cyclopropylmethyl)-N-[1-(2,4-difluorophenyl)-4-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-(cyclopropylmethyl)-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-ethyl-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine,-   3-(cyclopropylmethyl)-N-[cis-4-(2,4-difluorophenyl)cyclohexyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-(cyclopropylmethyl)-N-(2,3-dihydro-1H-inden-2-yl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-(cyclopropylmethyl)-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-ethyl-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   N-[cis-4-(2,4-difluorophenyl)cyclohexyl]-3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   3-(ethoxymethyl)-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine,-   3-(ethoxymethyl)-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine,-   8-chloro-3-(cyclopropylmethyl)-N-(cis-4-phenylcyclohexyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine,-   8-chloro-3-(cyclopropylmethyl)-N-(trans-4-phenylcyclohexyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine,-   trans-N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenylcyclopropanamine,-   N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine,-   (4*R)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine,-   (4*S)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine,-   (2S,4S)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenyltetrahydro-2H-pyran-4-amine,-   (2R,4R)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenyltetrahydro-2H-pyran-4-amine,    and-   cis-N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-4-phenyltetrahydrofuran-3-amine

Included within the scope of this list are stereoisomeric forms, thepharmaceutically acceptable salts and the solvates thereof.

The names of the compounds of the present invention were generatedaccording to the nomenclature rules agreed upon by the ChemicalAbstracts Service (CAS) using Advanced Chemical Development, Inc.,software (ACD/Name product version 10.01; Build 15494, 1 Dec. 2006) oraccording to the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC) using Advanced ChemicalDevelopment, Inc., software (ACD/Name product version 10.01.0.14105,October 2006). In case of tautomeric forms, the name of the depictedtautomeric form of the structure was generated. However it should beclear that the other non-depicted tautomeric form is also includedwithin the scope of the present invention.

DEFINITIONS

The notation “C₁₋₃alkyl” or “C₁₋₆alkyl” as used herein alone or as partof another group, defines a saturated, straight or branched, hydrocarbonradical having, unless otherwise stated, from 1 to 3 or 1 to 6 carbonatoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl,1-methyl-propyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl,1-pentyl, 1-hexyl and the like.

The notation “C₃₋₈cycloalkyl” as used herein alone or as part of anothergroup, defines a saturated, cyclic hydrocarbon radical having from 3 to8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

The notation “halogen” or “halo” as used herein alone or as part ofanother group, refers to fluoro, chloro, bromo or iodo, with fluoro orchloro being preferred.

The notation “C₁₋₃alkyl substituted with 1, 2 or 3 fluoro substituents”as used herein alone or as part of another group, and unless otherwisespecified, defines an alkyl group as defined above, substituted with 1,2 or 3 fluorine atoms, such as fluoromethyl; difluoromethyl;trifluoromethyl; 2,2,2-trifluoroethyl; 1,1-difluoroethyl;3,3,3-trifluoropropyl. Particular examples of these groups aretrifluoromethyl, 2,2,2-trifluoroethyl and 1,1-difluoroethyl.

The expression “(L-c) is not bound to the triazolopyridine core througha Carbon atom that is alpha to the Oxygen atom” as used herein, meansthat (L-c) is not bound to the triazolopyridine core through a Carbonatom that is adjacent to the Oxygen atom, i.e. the ether linkage in thering, thus when m^(c) is 0 and therefore, (L-c) represents atetrahydrofuran ring, or m^(e) is 1 and therefore, (L-c) represents atetrahydropyran ring, the following possibilities are available:

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, preferably from 1 to 3 hydrogens,more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

It will be appreciated that some of the compounds of formula (I) andtheir pharmaceutically acceptable addition salts and solvates thereofmay contain one or more centres of chirality and exist as stereoisomericforms.

Hereinbefore and hereinafter, the term “compound of formula (I)” ismeant to include the stereoisomers thereof. The terms “stereoisomers” or“stereochemically isomeric forms” hereinbefore or hereinafter are usedinterchangeably. The invention includes all stereoisomers of thecompound of Formula (I) either as a pure stereoisomer or as a mixture oftwo or more stereoisomers. Enantiomers are stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a racemate or racemic mixture. Diastereomers (ordiastereoisomers) are stereoisomers that are not enantiomers, i.e. theyare not related as mirror images. If a compound contains a double bond,the substituents may be in the E or the Z configuration. If a compoundcontains an at least disubstituted non aromatic cyclic group, thesubstituents may be in the cis or trans configuration. Therefore, theinvention includes enantiomers, diastereomers, racemates, E isomers, Zisomers, cis isomers, trans isomers and mixtures thereof.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved compounds whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other isomers. Thus, when a compound of formula (I)is for instance specified as (R), this means that the compound issubstantially free of the (S) isomer; when a compound of formula (I) isfor instance specified as E, this means that the compound issubstantially free of the Z isomer; when a compound of formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove or hereinafter are meant to comprise thetherapeutically active non-toxic acid and base addition salt forms whichthe compounds of Formula (I) are able to form. The pharmaceuticallyacceptable acid addition salts can conveniently be obtained by treatingthe base form with such appropriate acid. Appropriate acids comprise,for example, inorganic acids such as hydrohalic acids, e.g. hydrochloricor hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of Formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.primary, secondary and tertiary aliphatic and aromatic amines such asmethylamine, ethylamine, propylamine, isopropylamine, the fourbutylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline; the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely the salt formcan be converted by treatment with acid into the free acid form.

The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.

Some of the compounds according to formula (I) may also exist in theirtautomeric form. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ³H, ¹¹C,¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, theradioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person. Inparticular, the compounds can be prepared according to the followingsynthesis methods.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) may be converted into the corresponding diastereomeric saltforms by reaction with a suitable chiral acid. Said diastereomeric saltforms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of Formula (I) involves liquid chromatography using achiral stationary phase. Said pure stereochemically isomeric forms mayalso be derived from the corresponding pure stereochemically isomericforms of the appropriate starting materials, provided that the reactionoccurs stereospecifically.

A. Preparation of the Final Compounds Experimental Procedure 1

Final compounds according to Formula (I) can be prepared following artknown procedures by cyclization of intermediate compound of Formula (II)in the presence of a halogenating agent such as for example phosphorus(V) oxychloride (POCl₃) or trichloroacetonitrile-triphenylphosphinemixture in a suitable solvent such as for example DCE or CH₃CN stirredunder microwave irradiation, for a suitable period of time that allowsthe completion of the reaction, such as for example 50 min at atemperature between 140-200° C.

Alternatively, final compounds of Formula (I) can be prepared by heatingthe intermediate compound of Formula (II) for a suitable period of timethat allows the completion of the reaction, such as for example 1 h at atemperature between 140-200° C. In reaction scheme (1), all variablesare defined as in Formula (I).

Experimental Procedure 2

Final compounds according to Formula (I) can be prepared by art knownprocedures in analogy to the syntheses described in J. Org. Chem., 1966,31, 251, or J. Heterocycl. Chem., 1970, 7, 1019, by cyclization ofintermediate compounds of Formula (III) under suitable conditions in thepresence of a suitable ortho-ester of Formula (IV), wherein R¹ is asuitable substituent as defined for compounds of formula (I), like forexample, a methyl group, according to reaction scheme (2). The reactioncan be carried out in a suitable solvent such as, for example, xylene.Typically, the mixture can be stirred for 1 to 48 h at a temperaturebetween 100-200° C. In reaction scheme (2), all variables are defined asin Formula (I).

Alternatively, final compounds according to Formula (I) can be preparedby art known procedures in analogy to the synthesis described inTetrahedron Lett., 2007, 48, 2237-2240 by reaction of intermediatecompound of Formula (III) with carboxylic acids of Formula (V) or acidequivalents such as acid halides of Formula (VI) to afford finalcompounds of Formula (I). The reaction can be carried out using ahalogenating agent such as for exampletrichloroacetonitrile-triphenylphosphine mixture in the presence of asuitable solvent such as for example dichloroethane stirred at atemperature between 100-200° C. for 1 to 48 h or under microwaveirradiation for 20 min. In reaction scheme (2), all variables aredefined as in Formula (I).

Experimental Procedure 3

Final compounds according to Formula (I) can be prepared by art knownprocedures, by cyclization of intermediate compounds of Formula (VII)under suitable conditions in the presence of a suitable oxidising agentsuch as copper (II) chloride in a suitable solvent such as DMF, stirredfor 1 to 48 h at a temperature between r.t. and 200° C. In reactionscheme (3), all variables are defined as in Formula (I).

Experimental Procedure 4

Alternatively, final compounds according to Formula (I) can be preparedby reacting an intermediate of Formula (VIII) with an intermediate ofFormula (IX) under alkylating conditions that are known by those skilledin the art. This is illustrated in reaction scheme (4) wherein allvariables are defined as in mentioned hereinabove and X is a groupsuitable for alkylation reactions such as for example halo,methylsulfonate or p-tolylsulfonate. The reaction may be performed, forexample, in the presence of a suitable base such as for examplediisopropylethylamine in a suitable reaction solvent such as, forexample, DMF for a suitable period of time that allows the completion ofthe reaction at suitable temperature such as for example 120° C.

Experimental Procedure 5

The final compounds according to Formula (I) wherein the carbon betweenL and the triazolopyrimidine core is monosubstituted either with R³ orR⁴, hereby represented as (I-a), can be prepared by reacting anintermediate of Formula (X) with an intermediate of Formula (IX) underreductive amination conditions that are known by those skilled in theart. This is illustrated in reaction scheme (5) wherein all variablesare defined as in Formula (I). The reaction may be performed, forexample, in the presence of sodium triacetoxy borohydride in a suitablereaction-inert solvent such as, for example, 1,2-dichloroethane, at asuitable temperature, for example at temperature between r.t. and 150°C., under either classical heating or microwave irradiation, for asuitable period of time that allows the completion of the reaction.

B. Preparation of the Intermediates Experimental Procedure 6

Intermediate compounds according to Formula (II) can be preparedfollowing conditions that are known to those skilled in the art byreacting an intermediate of Formula (III) with a carboxylic acid ofFormula (V) via an amide bond formation reaction in the presence of asuitable coupling reagent. This is illustrated in reaction scheme (6)wherein all variables are defined as in Formula (I).

Alternatively, intermediate compounds according to Formula (II) can beprepared by art known procedures by reacting an intermediate of Formula(III) with a carboxylic acid of Formula (V). The reaction can be carriedout using a halogenating agent such as for example atrichloroacetonitrile-triphenylphosphine mixture in the presence of asuitable solvent such as for example dichloroethane stirred at atemperature between 100-200° C. for 1 to 48 h or under microwaveirradiation for 20 min. In reaction scheme (6), all variables aredefined as in Formula (I).

Alternatively, intermediate compounds according to Formula (II) can beprepared by art known procedures by reacting an intermediate of Formula(III) with an acid halide of formula (VI). The reaction can be carriedout using a inert-solvent such as for example DCM in the presence of abase such as for example TEA, for example at r.t. for a suitable periodof time that allows completion of the reaction. In reaction scheme (6),all variables are defined as in Formula (I).

Experimental Procedure 7

Intermediate compounds according to Formula (III) can be prepared byreacting an intermediate compound of Formula (XI) with hydrazineaccording to reaction scheme (7), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol or THFunder thermal conditions such as, for example, heating the reactionmixture for example at 160° C. under microwave irradiation for 20 min orclassical thermal heating at 90° C. for 16 h. In reaction scheme (7),all variables are defined as in Formula (I) and halo is chloro, bromo oriodo.

Experimental Procedure 8

Intermediate compounds according to Formula (VII) can be preparedfollowing conditions that are known to those skilled in the art byreacting an intermediate of Formula (III) with an aldehyde of Formula(XII) via imine bond formation reaction. The reaction can be carried outusing a protic solvent such as for example EtOH, for example attemperature between r.t. and 150° C. for a suitable period of time thatallows completion of the reaction. In reaction scheme (8), all variablesare defined as in Formula (I).

Experimental Procedure 9

Intermediate compounds according to Formula (XI) wherein the carbonbetween L and the triazolopyrimidine core is monosubstituted either withR³ or R⁴, hereby represented as (XI-a), can be prepared by reacting anintermediate of Formula (XIII) with an intermediate of Formula (IX)under reductive amination conditions that are known to those skilled inthe art. This is illustrated in reaction scheme (9) wherein allvariables are defined as in Formula (I). The reaction may be performed,for example, in the presence of triacetoxy borohydride in a suitablereaction-inert solvent such as, for example, DCE, at a suitabletemperature, typically at r.t., for a suitable period of time thatallows the completion of the reaction.

Experimental Procedure 10

Intermediate compounds according to Formula (XIII) can be prepared bysubjecting an intermediate of Formula (XIV) to conditions that are knownto those skilled in the art. This is illustrated in reaction scheme (10)wherein all variables are defined as mentioned hereinabove. The reactionmay be performed, for example, by first converting the aryl halide intoan aryl metal derivative where the metal may be lithium, magnesium,boron or zinc followed by reaction with the appropriate carbonylcompound. Methods accomplishing these transformations are well known tothose skilled in the art and include metal-halogen exchange with aGrignard reagent such as isopropylmagnesium chloride or strong base suchas for example BuLi in a suitable reaction inert solvent such as THF,diethyl ether or toluene, preferably THF at a temperature between −78°C. and 40° C., followed by reaction with the carbonyl compound such asfor example DMF at a temperature between −78° C. and 100° C.

Experimental Procedure 10a

Intermediate compounds according to Formula (X) can be prepared byreacting an intermediate of Formula (XV) under dihydroxylation andoxidative cleavage conditions that are known to those skilled in the artand can be realized for example with oxone, osmium tetroxide. Theprocess may be carried out optionally in a solvent such as 1,4-dioxane,water and generally at temperatures between about −100° C. and about100° C. A summary of such methods is found in “Comprehensive OrganicTransformations”, VCH Publishers, (1989), R. C. Larock, pp. 595-596.This is illustrated in reaction scheme (10a) wherein all variables aredefined as mentioned hereinabove.

Experimental Procedure 11

Intermediate compounds according to Formula (XV) can be prepared bycoupling reactions, such as Stille or Suzuki reactions, of anintermediate of Formula (XVI) with a compound of Formula (XVII) underconditions that are known to those skilled in the art. This isillustrated in reaction scheme (11) wherein all variables are defined asmentioned hereinabove, wherein M is trialkyltin, boronic acid orboronate ester, and a palladium catalyst. The process may be carried outoptionally in a solvent such as 1,4-dioxane, water and generally attemperatures between about r.t and about 200° C. in the presence of abase.

Experimental Procedure 12

Intermediate compounds according to Formula (XVI) can be preparedfollowing art known procedures by cyclization of an intermediatecompound of Formula (XVIII) in the presence of a halogenating agent suchas for example phosphorus (V) oxychloride (POCl₃) in a suitable solventsuch as, for example, dichloroethane, stirred under microwaveirradiation, for a suitable period of time that allows the completion ofthe reaction, as for example 5 min at a temperature between 140-200° C.In reaction scheme (12), all variables are defined as in Formula (I) andhalo is chloro, bromo or iodo.

Experimental Procedure 13

Intermediate compounds according to Formula (XVIII) can be prepared byart known procedures by reaction of a hydrazine intermediate of Formula(XIX) with acid halides of Formula (VI). The reaction can be carried outusing an inert-solvent, such as for example DCM, in the presence of abase such as for example triethylamine, for example at r.t. for asuitable period of time that allows completion of the reaction, forexample 20 min. In reaction scheme (13), all variables are defined as inFormula (I).

Experimental Procedure 14

Intermediate compounds according to Formula (XIX) can be prepared byreacting an intermediate compound of Formula (XX) with hydrazineaccording to reaction scheme (14), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol, THF or1,4-dioxane under thermal conditions such as, for example, heating thereaction mixture for example at 160° C. under microwave irradiation for30 min or classical thermal heating at 70° C. for 16 h. In reactionscheme (14), R² is defined as in Formula (I) and halo is chloro, bromoor iodo.

Experimental Procedure 15

Intermediate compounds according to Formula (XX) can be prepared byreacting an intermediate compound of Formula (XXI) with benzyl alcoholaccording to reaction scheme (15), a reaction that is performed in asuitable reaction-inert solvent, such as, for example,N,N-dimethylformamide in the presence of a suitable base, such as forexample sodium hydride at r.t. for a suitable period of time that allowsthe completion of the reaction, such as for example 1 h. In reactionscheme (15), R² is defined as in Formula (I) and halo is chloro, bromoor iodo.

Experimental Procedure 16

Intermediate compounds of Formula (XXI) wherein R² is trifluoromethyl,hereby named (XXI-a), can be prepared by reacting an intermediate ofFormula (XXI) wherein R² is iodine, hereby named (XXI-b), with asuitable trifluoromethylating agent, such as for examplefluorosulfonyl(difluoro)acetic acid methyl ester, according to reactionscheme (16). This reaction is performed in a suitable reaction-inertsolvent such as, for example, N,N-dimethylformamide in the presence of asuitable coupling agent such as for example, copper(I) iodide, underthermal conditions such as, for example, heating the reaction mixturefor example at 160° C. under microwave irradiation for 45 min. Inreaction scheme (16), halo is chloro, bromo or iodo.

Experimental Procedure 17

Intermediate compounds of Formula (XXI) wherein R² is cyclopropyl,hereby named (XXI-c), can be prepared by an ortho metallation strategyby reacting an intermediate of Formula (XXII) with a substituted orunsubstituted alkyl or an alkenyl halide (XXIII) in the presence of asuitable base, such as lithium diisopropylamide or butyllithium,according to reaction scheme (17) and following references: a)Tetrahedron 2001, 57(19), 4059-4090 or b) Tetrahedron 2001, 57(21),4489-4505. This reaction is performed in a suitable reaction-inertsolvent such as, for example, THF at low temperature such as, forexample −78° C. for a period of time that allows the completion of thereaction such as, for example 2-5 h. In reaction scheme (17), halo maybe chloro, bromo or iodo and E represents a cyclopropylradical. Ifrequired, intermediates (XXI-c) may be subjected to further simplefunctional group interconversion steps following art-known procedures tolead to the desirable final R² group.

Experimental Procedure 18

Intermediate compounds according to Formula (VIII) can be prepared fromconversion of the hydroxyl group present in intermediate compound ofFormula (XXIV) into a suitable leaving group such as for example halogenor mesylate under suitable conditions that are known to those skilled inthe art. The reaction may be performed, for example, by reacting anintermediate compound of Formula (XXIV) with methyl sulfonic acidchloride in the presence of a base such as triethylamine, pyridine orhalogenating reagens such as for example P(O)Br₃ in a suitablereaction-inert solvent such as, for example, DCM or DMF or mixtures ofboth, at a suitable temperature, typically at room temperature, for asuitable period of time that allows the completion of the reaction.

Experimental Procedure 19

Intermediate compounds according to Formula (XXIV) wherein the carbonbetween OH and the triazolopyrimidine core is monosubstituted eitherwith R³ or R⁴, hereby represented as (XXIV-a) can be prepared byreacting an intermediate of Formula (X) under conditions that are knownto those skilled in the art. This is illustrated in reaction scheme (19)wherein all variables are defined as mentioned hereinabove. The reactionmay be performed, for example, by reacting intermediate of Formula(XVII) with a reductive reagent such as for example sodium borohydridein a suitable solvent such as for example methanol. The reaction may beperformed at a suitable temperature, typically room temperature, for asuitable period of time that allows the completion of the reaction. Thisis illustrated in reaction scheme (19) wherein all variables are definedas mentioned hereinabove.

Experimental Procedure 20

Alternatively, intermediate compounds of Formula (XVI) can be preparedfollowing art known procedures by cyclization of intermediate compoundof Formula (XXV) under heating for a suitable period of time that allowsthe completion of the reaction, as for example 1 h at a temperaturebetween 140-200° C. In reaction scheme (20), all variables are definedas in Formula (I) and halo is chloro, bromo or iodo.

Experimental Procedure 21

Intermediate compounds according to Formula (XXV) can be prepared by artknown procedures by reaction of intermediate compounds of Formula (XXVI)with acid halides of Formula (VI). The reaction can be carried out usingan inert-solvent such as for example DCM in the presence of a base suchas for example triethylamine, for example at r.t. for a suitable periodof time that allows completion of the reaction, for example 20 min. Inreaction scheme (21), all variables are defined as in Formula (I) andhalo is chloro, bromo or iodo.

Experimental Procedure 22

Intermediate compounds according to Formula (XXVI) can be prepared byreacting an intermediate compound of Formula (XXVII) with hydrazineaccording to reaction scheme (22), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol, THF or1,4-dioxane under thermal conditions such as, for example, heating thereaction mixture for example at 160° C. under microwave irradiation for30 min or classical thermal heating at 70° C. for 16 h. In reactionscheme (22), R² is defined as in Formula (I) and halo is chloro, bromoor iodo.

Experimental Procedure 23

Intermediate compounds of Formula (IX) can be prepared by deprotectionof the nitrogen atom in an intermediate compound of formula (XXVIII),wherein PG represents a suitable protecting group for the nitrogen atom,such as for example tert-butoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, benzyl and methyl, according to reaction scheme (23)applying art known procedures. For example, when PG represents benzyl,then the deprotection reaction may be performed in a suitable reactioninert solvent, such as for example an alcohol, i.e. methanol, and1,4-cyclohexadiene, in the presence of a suitable catalyst, such as forexample palladium on charcoal, at a moderately high temperature such as,for example, 100° C. in a sealed vessel. Alternatively, when PGrepresents an alkyloxycarbonyl group, the deprotection reaction can beperformed by reaction with a suitable acid, such as for examplehydrochloric acid, in a suitable reaction-inert solvent, such as forexample 1,4-dioxane at a moderately high temperature, such as forexample reflux temperature. In reaction scheme (23), all variables aredefined as in formula (I).

The starting materials according to Formulae (IV), (V), (VI), (IX),(XII), (XVII) or (XXVIII) are compounds that are either commerciallyavailable or may be prepared according to conventional reactionprocedures generally known to those skilled in the art. For example,compounds of formula (IX), such as compounds with CAS numbers CAS1082662-38-1; CAS 1228117-53-0; CAS 109926-35-4; CAS 1035093-81-2; CAS2338-18-3; CAS 5769-08-4; CAS 5769-09-5; CAS 911826-56-7; CAS946413-75-8; CAS 173601-49-5; CAS 946125-04-8; CAS 548465-08-3; orprecursors thereof, such as CAS 183255-68-7; CAS 907997-17-5; CAS741260-53-7; CAS 1150633-65-0; and CAS 741260-59-3; are known in theart.

In order to obtain the HCl salts forms of the compounds, severalprocedures known to those skilled in the art can be used. In a typicalprocedure unless otherwise stated, for example, the free base can bedissolved in DIPE or Et₂O and subsequently, a 6N HCl solution in2-propanol or a 1 N HCl solution in Et₂O can be added dropwise. Themixture typically is stirred for 10 min after which the product can befiltered off. The HCl salt is usually dried in vacuo.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups. In case the functional groups ofintermediate compounds were blocked by protecting groups, they can bedeprotected after a reaction step.

Pharmacology

The compounds provided in this invention are positive allostericmodulators (PAMs) of metabotropic glutamate receptors, in particularthey are positive allosteric modulators of mGluR2. The compounds of thepresent invention do not appear to bind to the glutamate recognitionsite, the orthosteric ligand site, but instead to an allosteric sitewithin the seven transmembrane region of the receptor. In the presenceof glutamate or an agonist of mGluR2, the compounds of this inventionincrease the mGluR2 response. The compounds provided in this inventionare expected to have their effect at mGluR2 by virtue of their abilityto increase the response of such receptors to glutamate or mGluR2agonists, enhancing the response of the receptor.

As used herein, the term “treatment” is intended to refer to allprocesses, wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease, but does not necessarilyindicate a total elimination of all symptoms.

Hence, the present invention relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for use as a medicament.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms thereof and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, or apharmaceutical composition according to the invention for use in thetreatment or prevention of, in particular treatment of, a condition in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of allostericmodulators of mGluR2, in particular positive allosteric modulatorsthereof.

The present invention also relates to the use of a compound according tothe general Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament for the treatment or prevention of, inparticular treatment of, a condition in a mammal, including a human, thetreatment or prevention of which is affected or facilitated by theneuromodulatory effect of allosteric modulators of mGluR2, in particularpositive allosteric modulators thereof.

The present invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention foruse in the treatment, prevention, amelioration, control or reduction ofthe risk of various neurological and psychiatric disorders associatedwith glutamate dysfunction in a mammal, including a human, the treatmentor prevention of which is affected or facilitated by the neuromodulatoryeffect of positive allosteric modulators of mGluR2.

Also, the present invention relates to the use of a compound accordingto the general Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament for treating, preventing, ameliorating,controlling or reducing the risk of various neurological and psychiatricdisorders associated with glutamate dysfunction in a mammal, including ahuman, the treatment or prevention of which is affected or facilitatedby the neuromodulatory effect of positive allosteric modulators ofmGluR2.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancedependence/abuse, substance withdrawal (including substances such as,for example, opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder), mood disorders (includingdepression, major depressive disorder, treatment resistant depression,mania, bipolar disorders, such as bipolar mania), posttraumatic stressdisorder, trigeminal neuralgia, hearing loss, tinnitus, maculardegeneration of the eye, emesis, brain edema, pain (including acute andchronic states, severe pain, intractable pain, neuropathic pain, andpost-traumatic pain), tardive dyskinesia, sleep disorders (includingnarcolepsy), attention deficit/hyperactivity disorder, and conductdisorder.

In particular, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder,selected from the group of agoraphobia, generalized anxiety disorder(GAD), mixed anxiety and depression, obsessive-compulsive disorder(OCD), panic disorder, posttraumatic stress disorder (PTSD), socialphobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorderselected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder.

Preferably, the central nervous system disorder is a personalitydisorder selected from the group of obsessive-compulsive personalitydisorder and schizoid, schizotypal disorder.

Preferably, the central nervous system disorder is a substance abuse orsubstance-related disorder selected from the group of alcohol abuse,alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium,alcohol-induced psychotic disorder, amphetamine dependence, amphetaminewithdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence,nicotine withdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder,treatment resistant depression, bipolar depression, andsubstance-induced mood disorder.

Preferably, the central nervous system disorder is migraine.

Preferably, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy.

Preferably, the central nervous system disorder isattention-deficit/hyperactivity disorder.

Preferably, the central nervous disorder is selected from the group ofschizophrenia, behavioral and psychological symptoms of dementia, majordepressive disorder, treatment resistant depression, bipolar depression,anxiety, depression, generalised anxiety disorder, post-traumatic stressdisorder, bipolar mania, epilepsy, attention-deficit/hyperactivitydisorder, substance abuse and mixed anxiety and depression.

Preferably, the central nervous system disorder is a cognitive disorderselected from the group of delirium, substance-induced persistingdelirium, dementia, dementia due to HIV disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type, behavioral and psychological symptoms of dementia,substance-induced persisting dementia and mild cognitive impairment.

Of the disorders mentioned above, the treatment of psychosis,schizophrenia, behavioral and psychological symptoms of dementia, majordepressive disorder, treatment resistant depression, bipolar depression,anxiety, depression, generalised anxiety disorder, post-traumatic stressdisorder, bipolar mania, substance abuse and mixed anxiety anddepression, are or particular importance.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Therefore, the invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for use in the treatment of any one of the diseases mentionedhereinbefore.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms thereof and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, for usein treating any one of the diseases mentioned hereinbefore.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms thereof and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, for thetreatment or prevention, in particular treatment, of any one of thediseases mentioned hereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for the manufacture of a medicament for the treatment orprevention of any one of the disease conditions mentioned hereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for the manufacture of a medicament for the treatment of anyone of the disease conditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals,preferably humans, for the treatment or prevention of any one of thediseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from any one of the diseases mentioned hereinbefore, and amethod of preventing in warm-blooded animals, including humans, any oneof the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of a therapeuticallyeffective amount of a compound of Formula (I), a stereoisomeric formthereof and a pharmaceutically acceptable addition salt or solvatethereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the preventionand/or treatment of any one of the diseases mentioned hereinbeforecomprising administering a therapeutically effective amount of acompound according to the invention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effectiveamount of the PAMs of the present invention is the amount sufficient tomodulate the activity of the mGluR2 and that this amount varies interalia, depending on the type of disease, the concentration of thecompound in the therapeutic formulation, and the condition of thepatient. Generally, an amount of PAM to be administered as a therapeuticagent for treating diseases in which modulation of the mGluR2 isbeneficial, such as the disorders described herein, will be determinedon a case by case by an attending physician.

Generally, a suitable dose is one that results in a concentration of thePAM at the treatment site in the range of 0.5 nM to 200 μM, and moreusually 5 nM to 50 μM. To obtain these treatment concentrations, apatient in need of treatment likely will be administered an effectivetherapeutic daily amount of about 0.01 mg/kg to about 50 mg/kg bodyweight, preferably from about 0.01 mg/kg to about 25 mg/kg body weight,more preferably from about 0.01 mg/kg to about 10 mg/kg body weight,more preferably from about 0.01 mg/kg to about 2.5 mg/kg body weight,even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight,more preferably from about 0.1 to about 0.5 mg/kg body weight. Theamount of a compound according to the present invention, also referredto here as the active ingredient, which is required to achieve atherapeutically effect will, of course vary on case-by-case basis, varywith the particular compound, the route of administration, the age andcondition of the recipient, and the particular disorder or disease beingtreated. A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to admission. As described herein below,suitable pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients.

Because such positive allosteric modulators of mGluR2, includingcompounds of Formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds ofFormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of Formula (I), incombination with an mGluR2 agonist. Examples of mGluR2 agonists include,for example, LY-379268; DCG-IV; LY-354740; LY-404039; LY-544344;LY-2140023; LY-181837; LY-389795; LY-446433; LY-450477; talaglumetad;MGS0028; MGS0039; (+2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate;(+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid;(+)-2-amino-4-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid;1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo-[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid; (+)-4-amino-2-sulfonylbicyclo-[3.1.0]hexane-4,6-dicarboxylic acid;(+)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo-[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylicacid; or1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid. More preferable mGluR2 agonists include LY-379268; DCG-IV;LY-354740; LY-404039; LY-544344; or LY-2140023.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The present invention also provides compositions for preventing ortreating diseases in which modulation of the mGluR2 receptor isbeneficial, such as the disorders described herein. While it is possiblefor the active ingredient to be administered alone, it is preferable topresent it as a pharmaceutical composition. Accordingly, the presentinvention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable salt thereof, a solvate thereof or astereochemically isomeric form thereof. The carrier or diluent must be“acceptable” in the sense of being compatible with the other ingredientsof the composition and not deleterious to the recipients thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof, or anysubgroup or combination thereof may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). To preparethe pharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, for oral,topical, rectal or percutaneous administration, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, surfactants, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. Also included are solid form preparationsthat are intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, teaspoonfuls, tablespoonfuls, and segregated multiplesthereof.

Since the compounds according to the invention are orally administrablecompounds, pharmaceutical compositions comprising aid compounds for oraladministration are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

The amount of a compound of Formula (I) that can be combined with acarrier material to produce a single dosage form will vary dependingupon the disease treated, the mammalian species, and the particular modeof administration. However, as a general guide, suitable unit doses forthe compounds of the present invention can, for example, preferablycontain between 0.1 mg to about 1000 mg of the active compound. Apreferred unit dose is between 1 mg to about 500 mg. A more preferredunit dose is between 1 mg to about 300 mg. Even more preferred unit doseis between 1 mg to about 100 mg. Such unit doses can be administeredmore than once a day, for example, 2, 3, 4, 5 or 6 times a day, butpreferably 1 or 2 times per day, so that the total dosage for a 70 kgadult is in the range of 0.001 to about 15 mg per kg weight of subjectper administration. A preferred dosage is 0.01 to about 1.5 mg per kgweight of subject per administration, and such therapy can extend for anumber of weeks or months, and in some cases, years. It will beunderstood, however, that the specific dose level for any particularpatient will depend on a variety of factors including the activity ofthe specific compound employed; the age, body weight, general health,sex and diet of the individual being treated; the time and route ofadministration; the rate of excretion; other drugs that have previouslybeen administered; and the severity of the particular disease undergoingtherapy, as is well understood by those of skill in the area.

A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about300 mg taken once a day, or, multiple times per day, or one time-releasecapsule or tablet taken once a day and containing a proportionallyhigher content of active ingredient. The time-release effect can beobtained by capsule materials that dissolve at different pH values, bycapsules that release slowly by osmotic pressure, or by any other knownmeans of controlled release.

It can be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician will know how and when to start,interrupt, adjust, or terminate therapy in conjunction with individualpatient response.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs for use as a medicament or for use in the treatment,prevention, control, amelioration, or reduction of risk of diseases orconditions for which compounds of Formula (I) or the other drugs mayhave utility. The use of such a composition for the manufacture of amedicament as well as the use of such a composition for the manufactureof a medicament in the treatment, prevention, control, amelioration orreduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility are also contemplated.The present invention also relates to a combination of a compoundaccording to the present invention and an mGluR2 orthosteric agonist.The present invention also relates to such a combination for use as amedicine. The present invention also relates to a product comprising (a)a compound according to the present invention, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) a mGluR2orthosteric agonist, as a combined preparation for simultaneous,separate or sequential use in the treatment or prevention of a conditionin a mammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of mGluR2allosteric modulators, in particular positive mGluR2 allostericmodulators. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or diluents, or they may each be present in aseparate preparation together with pharmaceutically acceptable carriersor diluents.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Chemistry

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Hereinafter, “CI” means chemical ionisation; “DAD” means diode-arraydetector; “THF” means tetrahydrofuran; “DIPE” means diisopropylether;“DMF” means N,N-dimethylformamide; “DMSO” means dimethylsulfoxide;“EtOAc” means ethyl acetate; “DCM” or “CH₂Cl₂” means dichloromethane;“DCE” means dichloroethane; “DME” means 1,2-dimethoxyethane; “DIPEA”means N,N-diisopropylethylamine; “HPLC” means High Performance LiquidChromatography; “l” or “L” means liter; “LCMS” means Liquidchromatography/Mass spectrometry; “LRMS” means low-resolution massspectrometry/spectra; “HRMS” means high-resolution massspectra/spectrometry; “NH₄Ac” means ammonium acetate; “NH₄OH” meansammonium hydroxide; “NaHCO₃” means sodium hydrogencarbonate; “Et₂O”means diethyl ether; “MgSO₄” means magnesium sulphate; “EtOH” meansethanol; “ES” means electrospray; “Na₂SO₄” means sodium sulphate;“CH₃CN” means acetonitrile; “NaH” means sodium hydride; “MeOH” meansmethanol; “MS” means mass spectrometry; “NH₃” means ammonia; “Na₂S₂O₃”means sodium thiosulphate; “AcOH” means acetic acid; “Et₃N” or “TEA”mean triethylamine; “NH₄Cl” means ammonium chloride; “Pd/C” meansPalladium on activated charcoal; “Pd(PPh₃)₄” meanstetrakis(triphenylphosphine)-palladium(0); “PPh₃” meanstriphenylphosphine; “eq” means equivalent; “RP” means reverse phase;“r.t.” means room temperature; “Rt” means retention time; “mp” meansmelting point; “min” means minutes; “h” means hours; “s” meanssecond(s); “quant.” means quantitative; “sat.” means saturated“TOF”means time of flight.

Microwave assisted reactions were performed in a single-mode reactor:Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimodereactor: MicroSYNTH Labstation (Milestone, Inc.).

Thin layer chromatography (TLC) was carried out on silica gel 60 F254plates (Merck) using reagent grade solvents. Open column chromatographywas performed on silica gel, particle size 60 Å, mesh=230-400 (Merck)using standard techniques. Automated flash column chromatography wasperformed using ready-to-connect cartridges from Merck, on irregularsilica gel, particle size 15-40 μm (normal phase disposable flashcolumns) on a SPOT or LAFLASH system from Armen Instrument.

Intermediate 1 (I-1) 2,3-Dichloro-4-iodo-pyridine (I-1)

To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) indry Et₂O (150 ml) cooled at −78° C., under a nitrogen atmosphere, wasadded 2,2,6,6-tetramethyl-piperidine (11.64 ml, 69 mmol), dropwise. Theresulting reaction mixture was stirred at −78° C. for 10 min., and thena solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml)was added dropwise. The mixture was stirred at −78° C. for 30 min. andthen a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) wasadded. The mixture was allowed to warm to r.t. overnight, quenched withNa₂S₂O₃ (aqueous sat. solution) and extracted twice with EtOAc. Thecombined organic extracts were washed with NaHCO₃ (aqueous sat.solution), dried (Na₂SO₄) and concentrated in vacuo. The crude residuewas precipitated with heptane, filtered off and dried to yieldintermediate compound I-1 (8.21 g, 44%) as a pale cream solid.

Intermediate 2 (I-2) (3-Chloro-4-iodo-pyridin-2-yl) hydrazine (I-2)

To a solution of compound I-1 (8 g, 29.21 mmol) in 1,4-dioxane (450 ml),was added hydrazine monohydrate (14.169 ml, 175.255 mmol). The reactionmixture was heated in a sealed tube at 70° C. for 16 h. After cooling,NH₄OH (32% aqueous solution) was added and the resulting mixture wasconcentrated in vacuo. The white solid residue thus obtained was takenup in EtOH. The suspension thus obtained was heated and then filteredoff and the filtered solution cooled to r.t. The precipitate formed wasfiltered off and then the filtrate concentrated in vacuo to yieldintermediate compound I-2 (2.67 g, 52%) as a white solid.

Intermediate 3 (I-3)N′-(3-Chloro-4-iodo-pyridin-2-yl)-2-cyclopropylacetohydrazide (I-3)

To a solution of I-2 (0.73 g, 2.709 mmol) in dry DCM (8 ml), cooled at0° C., was added Et₃N (0.562 ml, 4.064 mmol) and cyclopropyl-acetylchloride (0.385 g, 3.251 mmol). The resulting reaction mixture wasstirred at r.t. for 16 h and then NaHCO₃ (aqueous sat. solution) wasadded. The resulting solution was extracted with DCM. The organic layerwas separated, dried (MgSO₄) and concentrated in vacuo to yieldintermediate compound I-3 (0.94 g, 99%).

Intermediate 4 (I-4)8-Chloro-3-cyclopropylmethyl-7-iodo[1,2,4]triazolo[4,3-a]pyridine (I-4)

I-3 (0.74 g, 2.389 mmol) was heated at 160° C. for 40 min. Aftercooling, the brown gum thus obtained was triturated with DIPE yieldingintermediate compound I-4 (0.74 g, 93%).

Intermediate 5 (I-5)7-Vinyl-3-cyclopropylmethyl-8-chloro[1,2,4]triazolo[4,3-a]pyridine (I-5)

To a solution of I-4 (12 g, 35.976 mmol), vinylboronic acid pinacolester (6.713 ml, 39.573 mmol) in NaHCO₃ (aqueous sat. solution, 90 ml)in 1,4-dioxane (360 ml) under a nitrogen atmosphere was added Pd(PPh₃)₄(2.079, 1.8 mmol). The resulting mixture was heated in a sealed tube at100° C. for 16 h. After cooling, the resulting reaction mixture wasdiluted with NaHCO₃ (aqueous sat. solution) and extracted with DCM. Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by column chromatography (silica; EtOAc in DCM0/100 to 80/20). The desired fractions were collected and concentratedin vacuo. The residue thus obtained was triturated with DIPE to yieldintermediate I-5 (6.09 g, 72%) as a yellow solid.

Intermediate 6 (I-6)8-Chloro-3-(cyclopropylmethyl)[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde(I-6)

To a solution of I-5 (6.09 g, 25.059 mmol) in 1,4-dioxane (320 ml)stirred at r.t. was added osmium tetroxide (2.5% in tert-butanol, 13.483ml, 1.042 mmol). Then a solution of sodium periodate (16.721 g, 78.177mmol) in water (80 ml) was added dropwise. The resulting mixture wasstirred at r.t. for 2 h, then, diluted with water and extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentratedin vacuo. The solid residue was triturated with Et₂O, filtered and driedin vacuo to yield intermediate I-6 (5.48 g, 89%) as a cream solid.

Intermediate 7 (I-7) 2,4-Dichloro-3-iodo-pyridine (I-7)

To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and DIPEA(3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at −78° C. under anitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6M in hexanes) dropwise. The resulting reaction mixture was stirred at−78° C. for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol)in dry THF (20 mL) was added dropwise. The mixture was stirred at −78°C. for 1 h., allowed to warm to r.t., diluted with EtOAc and quenchedwith NH₄Cl (aqueous sat. solution) and Na₂S₂O₃ (aqueous sat. solution).The organic layer was separated, washed with NaHCO₃ (aqueous sat.solution), dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (silica gel; DCM in heptane 0/100to 20/80). The desired fractions were collected and concentrated invacuo to yield intermediate compound I-7 (7.8 g, 81%).

Intermediate 8 (I-8) 2,4-Dichloro-3-trifluoromethyl-pyridine (I-2)

To a mixture of compound I-7 (2 g, 7.30 mmol) in DMF (50 mL) were addedfluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reactionmixture was heated in a sealed tube at 100° C. for 5 h. After cooling,the solvent was evaporated in vacuo. The crude product was purified bycolumn chromatography (silica gel, DCM). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound I-8(1.5 g, 95%).

Intermediate 9 (I-9) 4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine(I-9)

To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50mL) cooled at 0° C., was added benzyl alcohol (1.26 mL, 12.2 mmol). Theresulting mixture was stirred for 2 min. then; intermediate compound I-8(2.5 g, 11.57 mmol) was added. The resulting reaction mixture wasgradually warmed to r.t. and stirred for 1 h. The reaction mixture wasquenched with water and extracted with Et₂O. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (silica gel; DCM in Heptane 0/100to 100/0). The desired fractions were collected and concentrated invacuo to yield intermediate compound I-9 (1.1 g, 33%).

Intermediate 10 (I-10)4-(Benzyloxy)-2-hydrazino-3-(trifluoromethyl)pyridine (I-10)

To a suspension of compound I-9 (1.09 g, 3.79 mmol) in 1,4-dioxane (9mL), was added hydrazine monohydrate (3.67 mL, 75.78 mmol). The reactionmixture was heated at 160° C. under microwave irradiation for 30 min.After cooling, the resulting solution was concentrated in vacuo. Theresidue thus obtained was dissolved in DCM and washed with NaHCO₃(aqueous sat. solution). The organic layer was separated, dried (Na₂SO₄)and concentrated in vacuo to yield intermediate compound I-10 (0.89 g,83%) as a white solid.

Intermediate 11 (I-11) N′-[4-(Benzyloxy)-3-(trifluoromethyl)pyridin-2-yl]-2-cyclopropylacetohydrazide (I-11)

To a solution of I-10 (0.89 g, 3.14 mmol) in dry DCM (3 mL) was addedEt₃NH (0.65 mL, 4.71 mmol) and cyclopropyl-acetyl chloride [C.A.S.543222-65-5] (0.37 g, 3.14 mmol). The resulting reaction mixture wasstirred at 0° C. for 20 min. The resulting mixture was then concentratedin vacuo to yield intermediate compound I-11 (1.1 g, 96%).

Intermediate 12 (I-12) Propionic acidN′-(4-benzyloxy-3-trifluoromethyl-pyridin-2-yl)-hydrazide (I-12)

Intermediate I-12 was synthesized following the same approach describedfor intermediate I-11. Starting from I-10 (3.2 g, 11.3 mmol) andreplacing cyclopropyl chloride for propionyl chloride. The reactionmixture was stirred at r.t. for 18 h yielding intermediate I-12 (2.3 g,59.7%) as white solid.

Intermediate 13 (I-13) Ethoxy-acetic acidN′-(4-benzyloxy-3-methyl-pyridin-2-yl)-hydrazide (I-13)

Intermediate I-13 was synthesized following the same approach describedfor intermediate I-11. Starting from I-10 (4 g, 14.12 mmol) andreplacing cyclopropyl chloride for ethoxy-acetyl chloride, intermediateI-13 (5 g, 96%) was obtained. The compound was used without purificationfor the next step.

Intermediate 14 (I-14)7-Chloro-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(I-14)

I-11 (1.14 g, 1.87 mmol) and phosphorous (V) oxychloride (0.35 g, 3.74mmol) in CH₃CN (10 mL) were heated at 150° C. under microwaveirradiation for 10 min. After cooling, the resulting reaction mixturewas diluted with DCM and washed with NaHCO₃ (aqueous sat. solution),dried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel; 7M solution of NH₃ in MeOH in DCM0/100 to 20/80). The desired fractions were collected and concentratedin vacuo to yield intermediate compound I-14 (0.261 g, 51%) as a whitesolid.

Intermediate 15 (I-15)7-Chloro-3-ethoxymethyl-8-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridine(I-15)

Intermediate I-15 was synthesized following the similar approachdescribed for intermediate I-14. Starting from I-13 (12.4 g, 30.3 mmol)and DIPEA (6.35 ml, 36.45 mmol), intermediate I-15 (2.5 g, 29.8%) wasobtained as light brown solid.

Intermediate 16 (I-16)7-Chloro-3-Ethyl-8-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridine (I-16)

Intermediate I-16 was synthesized following similar approach describedfor intermediate I-14. Starting from I-12 [2.3 g (80% pure), 5.4 mmol]and DIPEA (0.707 ml, 4.039 mmol), intermediate I-16 (1.12 g, 83%) asbrown solid was obtained.

Intermediate 17 (I-17)7-Vinyl-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(I-17)

A suspension of I-14 (1.65 g, 5.986 mmol), vinylboronic acid pinacolester (1.218 ml, 7.183 mmol), Pd(PPh₃)₄ (0.346, 0.3 mmol) and NaHCO₃(aqueous sat. solution, 12.5 ml) in 1,4-dioxane (64.5 ml) was heated at150° C. under microwave irradiation for 13 min. After cooling, theresulting reaction mixture was diluted with EtOAc/water and filteredthrough diatomaceous earth. The filtrate was washed with water and NaCl(aqueous sat. solution) and extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified again by column chromatography (silica; EtOAc in DCM from 0/100to 40/60). The desired fractions were collected and concentrated invacuo to yield intermediate I-17 (1.34 g, 83.7%).

Intermediate 18 (I-18)3-Ethyl-8-trifluoromethyl-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (I-18)

Intermediate I-18 was synthesized following the same approach describedfor intermediate I-17. Starting from I-16 (2.8 g, 15.22 mmol),intermediate I-18 (4 g, 94%) was synthesized as cream solid.

Intermediate 19 (I-19)3-Ethoxymethyl-8-trifluoromethyl-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine(I-19)

Intermediate I-19 was synthesized following the same approach describedfor intermediate I-17. Starting from I-15 (4 g, 14.3 mmol), intermediateI-19 (quant. yield) was obtained as light brown solid.

Intermediate 20 (I-20)7-Carboxaldehyde-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(I-20)

A solution of I-17 (6.24 g, 21.014 mmol), sodium periodate (13.484 g,63.041 mmol), osmium tetroxide (2.5% in tert-butanol, 10.873 ml, 0.841mmol) in water (55 ml) and 1,4-dioxane (221 ml) was stirred at r.t. for2 h. The resulting reaction mixture was diluted with EtOAc/water andfiltered through diatomaceous earth. The filtrate was extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentratedin vacuo. The solid residue was washed with Et₂O, filtered and dried invacuo to yield intermediate I-20 (3.84 g, 67.9%).

Intermediate 21 (I-21)3-Ethyl-8-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde(I-21)

Intermediate I-21 was synthesized following the same approach describedfor intermediate I-20. Starting from I-18 (4 g, 16.5 mmol), intermediateI-21 (1.88 g, 46.6%) as cream solid was obtained.

Intermediate 22 (I-22)3-Ethoxymethyl-8-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde(I-22)

Intermediate I-22 was synthesized following the same approach describedfor intermediate I-20. Starting from I-19 (3.88 g, 14.3 mmol),intermediate I-22 (2.2 g, 56.7%) as light brown solid was obtained.

Intermediate 23 (I-23)7-Hydroxymethyl-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(I-23)

To a solution of I-20 (1.73 g, 6.426 mmol) in MeOH (58 ml) stirred at 0°C., was added portionwise sodium borohydride (0.243, 6.426 mmol). Theresulting mixture was stirred at r.t. for 1 h. The resulting mixture wasconcentrated in vacuo. The residue was treated with water and NaCl(aqueous sat. solution) and extracted with EtOAc. The organic layer wasseparated and concentrated in vacuo. The residue was purified by columnchromatography (silica; MeOH/NH₃ in DCM 0/100 to 5/95). The desiredfractions were collected and concentrated in vacuo to yield intermediateI-23 (1.015 g, 58%) as brown syrup.

Intermediate 24 (I-24)7-(Methylsulfonyloxy)methyl-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo-[4,3-a]pyridine(I-24)

To a solution of I-23 (1.341 g, 9.678 mmol) and Et₃N (0.778 ml, 5.612mmol) in DCM (42 ml) stirred at 0° C., was added dropwise methylsulfonylchloride (0.749 ml, 9.678 mmol) and stirred at r.t. for 2 h. Theresulting mixture was treated with NaHCO₃ (aqueous sat. solution) andextracted with DCM. The organic layer was separated and concentrated invacuo to yield intermediate I-24 (2.6 g, 87%).

Intermediate 25 (I-25) Trifluoro-methanesulfonic acid1,4-dioxa-spiro[4.5]dec-7-en-8-yl ester (I-25)

n-Butyllithium (2.5 M in THF, 8.64 mL, 21.6 mmol) was added dropwise toa solution of DIPEA (3.12 mL, 22.26 mmol) in 12 ml of THF at −78° C. andunder nitrogen atmosphere. The mixture was stirred for 15 min and then,a solution of 1,4-cyclo-hexanedione monoethylene acetal (3 g, 19.208mmol) in 15 ml of THF was added dropwise. The mixture was stirred at−78° C. for 1 hour. Then, a solution ofN-phenyl-trifluoromethanesulfonimide (6.924 g, 19.381 mmol) in 15 ml ofTHF was added and the mixture was kept in an ice-water bath and thenallowed to warm to r.t. and stirred for 16 h. The mixture was evaporatedin vacuo, the crude product was purified by short open column (silica;EtOAc in heptane 0/100 to 15/85), the desired fractions were collectedand concentrated in vacuo to yield intermediate I-25 (6.13 g, 89%purity) as light brown oil which was used in the next reaction stepwithout any further purification.

Intermediate 26 (I-26)8-(2,4-Difluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-7-ene (I-26)

A mixture of intermediate I-25 (6.11 g, 89% pure, 18.86 mmol),2,4-difluorophenyl-boronic acid (4.55 g, 28.86 mmol), LiCl (3.26 g, 1.41mmol), Na₂CO₃ (8.1 g, 76.46 mmol), in DME (70.2 mL) and H₂O (38 mL) wasdeoxygenated with a nitrogen flow. Then,tetrakis(triphenylphosphine)palladium (0) (1.63 g, 1.41 mmol) was addedand the mixture was stirred under nitrogen atmosphere, at reflux for 5hours. After cooling, the mixture was diluted with EtOAc/H₂O andfiltered off over diatomaceous earth. The filtrate was washed withsaturated NaHCO₃ and extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was purified by two flash columnchromatographies (silica; EtOAc in heptane 0/100 to 5/95, then silica;CH₂Cl₂ 100%). The desired fractions were collected and concentrated invacuo to yield intermediate I-26 (1.56 g, 32.7%) as oil.

Intermediate 27 (I-27) 4-(2,4-Difluoro-phenyl)-cyclohexanone (I-27)

A solution of intermediate I-26 (1.5 g, 5.89 mmol) in HCl (5 M in H₂O,26 mL) and THF (26 mL) was stirred at reflux for 4 h. The mixture wascooled with an ice-water bath, basified with Na₂CO₃ and extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄), filtered and thesolvent evaporated in vacuo. The crude product was purified by flashcolumn chromatography (silica; EtOAc in heptane 0/100 to 15/85). Thedesired fractions were collected and concentrated in vacuo, to yieldintermediate I-27 as colorless oil that solidified upon standing.

Intermediate 28 (I-28)cis-Benzhydryl-[4-(2,4-difluoro-phenyl)-cyclohexyl]-amine (I-28)

A mixture of intermediate I-27 (1.05 g, 4.99 mmol), benzhydrylamine(0.94 mL, 5.49 mmol) in DME (30 mL) was stirred at r.t. for 16 h. Then,sodium triacetoxy-borohydride (1.58 g, 7.49 mmol) was added and themixture was stirred at r.t. for 4 days. The mixture was treated withsaturated Na₂CO₃ at 0° C. and extracted with EtOAc. The organic layerwas separated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was purified by flash column chromatography(silica; EtOAc in heptane 10/90). The desired fractions were collectedand concentrated in vacuo to yield intermediate I-28 (1.32 g, 70%) ascolorless oil that solidified upon standing.

Intermediate 29 (I-29) cis-4-(2,4-Difluoro-phenyl)-cyclohexylamine(I-29)

A mixture of intermediate I-28 and Palladium on activated carbon 10%(1.18 g, 3.47 mmol) in HCO₂H/MeOH 4.4% (60 mL) was stirred at r.t.overnight. The cooled crude reaction was filtered off over diatomaceousearth and the catalyst washed with MeOH and MeOH/NH₃. The filtrate wasevaporated till dryness and the residue purified by open columnchromatography (silica; MeOH/NH₃ in CH₂Cl₂ 0/100 and 15/85). The desiredfractions were collected and concentrated in vacuo to yield intermediateI-29 (0.67 g, 91.3%) as white solid.

Intermediate 30 (I-30) cis-4-(2,4-Difluoro-phenyl)-cyclohexanol (I-30)

To a solution of intermediate I-27 (1.36 g, 6.46 mmol) in THF (17 mL),cooled at −78° C. and under nitrogen atmosphere, was added dropwiseL-Selectride® (7.18 mL, 7.18 mmol) and the resulting reaction mixturewas stirred at −78° C. for 2 h and at r.t. overnight. Then moreL-Selectride® (1.3 ml) was added at −78° C. and the mixture was stirredat −78° C. for 2 h and at r.t. for additional 2 h. The cooled crudereaction was quenched dropwise with water, followed by NaOH (1M in H₂O,13.12 ml) and aqueous H₂O₂ (13.12 ml). The mixture was diluted withsaturated Na₂CO₃ (197 ml) and extracted with Et₂O (3×70 ml). The organiclayer was separated, dried (Na₂SO₄), filtered and evaporated in vacuo.The residue was purified by flash chromatography (silica; EtOAc inheptane 0:100 to 20:80) yielding I-30 (0.72 g, 70%).

Intermediate 31 (I-31) cis-Methanesulfonic acid4-(2,4-difluoro-phenyl)-cyclohexyl ester (I-31)

To a solution of intermediate I-30 (0.97 g, 4.57 mmol) and Et₃NH (1.26ml, 9.14 mmol) in DCM (20 mL), cooled with an ice-water bath,methanesulfonyl chloride (0.531 mL, 6.85 mmol) was added dropwise andthe resulting reaction mixture was stirred for 2 h. The crude reactionwas washed with water and brine, extracted with CH₂Cl₂, dried (Na₂SO₄),filtered and evaporated under vacuo to yield intermediate I-31 (1.52 g,87% purity). The residue was used in the next reaction step without anyfurther purification.

Intermediate 32 (I-32) trans-1-(4-Azido-cyclohexyl)-2,4-difluoro-benzene(I-32)

A mixture of intermediate I-31 (0.892 g, 87% pure, 2.67 mmol), sodiumazide (0.265 g, 4 mmol) in DMSO (9 mL) was heated at 120° C. for 10 minunder microwave irradiation. The mixture was washed with water,extracted with EtOAc, the organic layer separated, dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by flash chromatography(silica; EtOAc in heptanes 0:100 to 4:96) the desired fraction collectedand evaporated affording intermediate I-32 (76.8% yield).

Intermediate 33 (I-33) trans-4-(2,4-Difluoro-phenyl)-cyclohexylamine(I-33)

A suspension of intermediate I-32 (0.685 g, 2.88 mmol) and Pd/C in EtOH(20 mL) was hydrogenated (atmospheric pressure), at r.t. overnight. Thecrude mixture was filtered off over diatomaceous earth and the filtratewas evaporated in vacuo yielding intermediate I-33 (0.52 g, 85%), thatwas used as such in the next reaction step.

Intermediate 34 (I-34)7-(Chloromethyl)-3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]-pyridine(I-34)

To a solution of I-23 (0.376 g, 1.39 mmol) in CH₂Cl₂ (4 mL) in a sealedtube at 0° C., were added portionwise pyridine (0.336 mL, 4.16 mmol)followed by p-toluenesulfonyl chloride 0.529 g, 0.77 mmol) and themixture was stirred at room temperature for 24 h. The mixture wastreated with HCl (2 N) and extracted with CH₂Cl₂. The organic layer wasseparated, dried (Na₂SO₄), filtered and evaporated in vacuo. The crudeproduct was purified by flash column chromatography (silica; MeOH/NH₃ inCH₂Cl₂ 0/100 and 4/96). The desired fractions were collected andconcentrated in vacuo to yield intermediate I-34 (114.3 mg, 28%) as apale yellow solid.

Intermediate 35 (I-35)3-(Cyclopropylmethyl)-7-(iodomethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]-pyridine(I-35)

Method A

A mixture of I-34 (0.114 g, 0.40 mmol), NaI (0.237 g, 1.58 mmol) andacetone (8.4 mL) in a sealed tube was stirred at reflux for 1 h. Themixture was concentrated, diluted with water and extracted with CH₂Cl₂.The organic layer was separated, dried (Na₂SO₄), filtered and thesolvent evaporated till dryness. The residue was used in the next stepwithout further purification.

Method B

A mixture of I-24 (16.485 mg, 0.05 mmol), NaI (28.29 mg, 0.19 mmol) andacetone (1 mL) in a sealed tube was stirred at reflux for 1 h. Themixture was concentrated, diluted with water and extracted with CH₂Cl₂.The organic layer was separated, dried (Na₂SO₄), filtered and thesolvent evaporated till dryness. The residue was used in the next stepwithout further purification.

Intermediate 36 (I-36) (4E)-2,3-Dihydro-4H-chromen-4-one oxime (I-36)

Sodium acetate (503.852 mg, 6.14 mmol) was added to a stirred solutionof 4-chromanone ([CAS491-37-2], 700 mg, 4.73 mmol) and hydroxylaminehydrochloride ([CAS5470-11-1], 426.808 mg, 6.14 mmol) in EtOH (31 mL).The mixture was stirred at 80° C. for 16 h. The mixture was cooled toRT, diluted with EtOAc, and washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated in vacuo to yieldI-36 (727.7 mg, 93%) as a white solid, which was used in the next stepwithout further purification.

Intermediate 37 (I-37) 3,4-Dihydro-2H-chromen-4-amine (I-37)

A solution of I-36 (727.7 mg, 4.46 mmol) in NH₃ (7 N in MeOH, 85 mL, 595mmol) was hydrogenated in a H-cube reactor (1.5 mL/min, 70 mm, Raney NiCartridge, full H₂ mode, 80° C., 1 cycle). The product was evaporated invacuo to yield I-37 as a green oil, which was used without furtherpurification.

Intermediate 38 (I-38) Cis-2-Phenyltetrahydro-2H-pyran-4-ol (I-38)

Sulfuric acid (1.05 mL, 19.70 mmol) was added dropwise to a stirredsuspension of 3-buten-1-ol (1.79 mL, 20.80 mmol) and benzaldehyde (neat,1.076 mL, 10.59 mmol) at 5° C. and the mixture was stirred at RT for 16h. Ice water was added to the mixture; the mixture was then basifiedwith 1N NaOH and extracted with EtOAc. The organic layer was separated,dried (Na₂SO₄) and evaporated in vacuo to give a crude product that waspurified by flash chromatography (silica; MeOH in DCM 0/100 to 5/95).The desired fractions were collected and the solvents evaporated invacuo to give I-38 (600 mg, 16%) as a brown oil.

Intermediate 39 (I-39) Cis-2-Phenyltetrahydro-2H-pyran-4-ylmethanesulfonate (I-39)

DIPEA (1.95 mL, 11.32 mmol) and methanesulfonyl chloride (350 mg, 3.06mmol) were added to stirred suspension of I-38 (540 mg, 2.58 mmol) inDCM (10 mL) at 0° C. and the mixture was stirred at RT for 2 h. Themixture was diluted with water and brine and extracted with DCM. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventsevaporated in vacuo to give I-39 as a brown oil.

Intermediate 40 (I-40) Trans-4-Azido-2-phenyltetrahydro-2H-pyran (I-40)

Sodium azide (8 g, 121.18 mmol) was added to a stirred suspension ofI-39 (10 g, 31.21 mmol) in DMF (128.5 mL) and the mixture was stirred at100° C. for 4 h. The mixture was then diluted with water and brine andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo to give a crude that waspurified by chromatography (silica; DCM 100%). The desired fractionswere collected and the solvents evaporated in vacuo to give I-40 (6.6 g)as a yellow foam.

Intermediates 41 (I-41), 41a (I-41a) and 41b (I-41b)Trans-2-Phenyltetrahydro-2H-pyran-4-amine (I-41),(2*R,4*R)-2-phenyltetrahydro-2H-pyran-4-amine (I-41a), (2*S,4*S)-2-phenyltetrahydro-2H-pyran-4-amine (I-41b)

A solution of I-40 (6.6 g, 32.31 mmol) in EtOH (200.87 mL) washydrogenated with Pd (145.459 mg, 1.37 mmol) as catalyst, at RT andnormal pressure, overnight. The crude reaction was filtered off overdiatomaceous earth and the filtrate was evaporated till dryness. Theresidue was purified by flash chromatography (silica; MeOH in DCM 0/100to 10/90). The desired fractions were collected and the solventsevaporated in vacuo to give I-41 (1.3 g, 23%) as a yellow oil.

I-41 was then purified by chiral SFC on CHIRALPAK AD-H 5 μm 250×20 mm,mobile phase: 0.3% isopropylamine, 80% CO₂, 20% MeOH, yielding I-41a(563 mg, 10%) and I-41b (610 mg, 11%) as a cream solid.

Intermediate 42 (I-42) Trans-4-Phenyltetrahydrofuran-3-ol

3,4-Epoxytetrahydrofuran (3.9 g, 45.30 mmol) in dry THF (9 mL) was addeddropwise to a stirred suspension of phenylmagnesium bromide (15.1 mL,45, 30 mmol), CuI (604.13 mg, 3.17 mmol) and dry THF (5 mL) undernitrogen at 0° C. and the mixture was stirred at RT for 3 h. The mixturewas diluted with sat. aq. NH₄Cl and extracted with EtOAc. The organiclayer was separated, dried (Na₂SO₄), filtered and evaporated in vacuo.

A second batch was obtained according to the above procedure reacting3,4-epoxy-tetrahydrofuran (1.0 g, 11.62 mmol), phenylmagnesium bromide(3.872 mL, 11.62 mmol), CuI (155.67 mg, 0.813 mmol) and dry THF (totalvolume of 3.6 mL). The residues obtained from the above two batches wasmixed and purified by flash chromatography (silica; DCM in MeOH 0/100 to10/90). The desired fractions were collected and evaporated in vacuo togive I-42 (5.5 g, 74%) as a yellow oil.

Intermediate 43 (I-43) (4S)-4-Phenyldihydrofuran-3 (2H)-one (I-43)

A solution of I-42 (2.02 g, 12.30 mmol) in DCM was passed through acartridge of Chromium(VI) oxide (50 g Jones Reagent on silica 0.6mmol/gr, 2.609 g, 24.60 mmol) at 5 mL/min at RT. The reaction solutionwas evaporated to yield I-43 (1.36 g, 68%) as a brown oil.

Intermediate 44 (I-44) Cis-N-Benzyl-4-phenyltetrahydrofuran-3-amine(I-44)

Benzylamine (0.859 g, 8.02 mmol) was added dropwise to a stirredsuspension of I-43 (1 g, 6.17 mmol) in dry DCM (25 mL) and the mixturewas stirred at RT for 40 min. After this time, acetic acid (352.97 μL,6.17 mmol) and sodium triacetoxyborohydride (1.96 g, 9.25 mmol) wereadded and the mixture was stirred at RT for 18 h. The mixture wasdiluted with water and extracted with DCM. The organic layer wasseparated, dried (Na₂SO₄), filtered and evaporated in vacuo to give I-44(500 mg, 32%) as a brown oil.

Intermediate 45 (I-45) Cis-N-Benzyl-4-phenyltetrahydrofuran-3-amine(I-45)

A solution of I-44 (500 mg, 1.97 mmol) in EtOH (40 mL) was hydrogenatedin a H-Cube reactor (1.5 mL/min. (70 mm) Pd(OH)₂/C cartridge, 1.97 mmol,full H₂, 80° C., 1 cycle). The solvent was evaporated in vacuo to give aresidue which was purified by flash chromatography (silica; 7 M solutionof NH₃ in MeOH in DCM 0/100 to 10/90). The desired fractions werecollected and the solvents evaporated in vacuo to give I-45 (212.4 mg,66%) as a yellow oil.

Final Products Example 1 (E-1)3-(Cyclopropylmethyl)-N-[trans-4-(2,4-difluorophenyl)cyclohexyl]-8-(trifluoro-methyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-1)

Intermediate I-20 (0.11 g, 0.409 mmol) was added to a solution ofintermediate I-33 (0.103 g, 0.49 mmol) in DCE (2.4 mL) and the mixturewas stirred at r.t. for 2 h. Then, AcOH (0.041 mL) and sodiumtriacetoxyborohydride (0.095 g, 0.44 mmol) were added and the mixturewas stirred at r.t. for 18 h. Then more sodium triacetoxyborohydride(1.1 equiv., 0.095 g) was added the mixture stirred for additional 2 h.After this time more sodium triacetoxyborohydride (0.55 equiv., 0.047 g)was added again and the stirring was continued for 2 h more. The mixturewas then treated with satured NaHCO₃ and extracted with CH₂Cl₂. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventsevaporated in vacuo. The crude product was purified twice by flashcolumn chromatography (silica; MeOH/NH₃ in CH₂Cl₂ 0/100 to 4/96). Thedesired fractions were collected and concentrated in vacuo. Finally, theproduct was triturated with DIPE, filtered and dried to yield productE-1 (0.085 g, 45%) as white solid compound. M.P. 110.1° C. (Mettler FP81HT/FP90).

Example 2 (E-2)3-(Cyclopropylmethyl)-N-[1-(2,4-difluorophenyl)-4-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-2)

Intermediate I-20 (0.11 g, 0.41 mmol) was added to a solution of1-(2,4-difluoro-phenyl)piperidin-4-amine [(C.A.S. 1016777-81-3), 0.133g, 0.49 mmol] in DCE (2.4 mL) and the mixture was stirred at r.t. for 2h. Then, AcOH (0.041 mL) and sodium triacetoxyborohydride (0.095 g, 0.45mmol) were added and the mixture was stirred at r.t. for 18 h. Afterthat, more sodium triacetoxyborohydride (0.8 equiv., 0.069 g) was addedand the mixture was stirred at r.t. for additional 2 h. The mixture wastreated with satured NaHCO₃ and extracted with CH₂Cl₂. The organic layerwas separated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was purified twice by column chromatography(silica; EtOAc in CH₂Cl₂ 0/100 to 100/0; then MeOH in CH₂Cl₂ 0/100 to5/95). The desired fractions were collected and concentrated in vacuo.Finally, the product was triturated with DIPE, filtered and dried toyield E-2 (0.079 g, 41.3%) as white solid compound. M.P. 118.2° C.(Mettler FP 81HT/FP90).

Example 3 (E-3)3-(Cyclopropylmethyl)-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-3)

A solution of intermediate I-24 (0.25 g, 0.64 mmol) in CH₃CN (4 ml) wasadded to a stirred solution of trans-4-Phenylcyclohexylamine [(C.A.S.5769-10-8), 0.14 g, 0.8 mmol] and DIPEA (0.166 mL, 0.961 mmol) in CH₃CN(4 ml) in a sealed tube. The mixture was stirred at 85° C. for 6 h andthen the solvent evaporated in vacuo. The crude product was purifiedtwice by column chromatography (silica; MeOH/NH₃ in CH₂Cl₂ 0/100 to5/95; and then EtOAc in CH₂Cl₂ 0/100 to 100/0). The desired fractionswere collected and concentrated in vacuo to yield the desired compoundonly 63% pure. Thus the mixture was purified again by RP HPLC on C18XBridge™ (30×100 5 μm), mobile phase (Gradient from 80% 0.1%NH₄CO₃H/NH₄OH pH 9 solution in Water, 20% CH₃CN to 0% 0.1% NH₄CO₃H/NH₄OHpH 9 solution in Water, 100% CH₃CN) yielding E-3 (0.034 g, 12.2%) aswhite solid.

Example 4 (E-4)3-Ethyl-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]-pyridine-7-methanamine(E-4)

Sodium triacetoxyborohydride (0.104 g, 0.49 mmol) was added to a stirredsolution of I-21 (0.1 g, 0.33 mmol, 80% pure) andtrans-4-Phenylcyclohexylamine [(C.A.S. 5769-10-8), 0.069 g, 0.39 mmol]in DCE (3.5 mL). The mixture was heated at 120° C. for 20 min undermicrowave irradiation. Then it was treated with satured NaHCO₃ andextracted with CH₂Cl₂. The organic layer was separated, dried (Na₂SO₄),filtered and the solvent evaporated in vacuo. The crude mixture was thensuspended in MeOH (3.5 mL) and sodium borohydride (0.013 g, 0.39 mmol)was added. The mixture was stirred at r.t. for 5 h. The organic layerwas separated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was purified by flash column chromatography(silica; 7N solution of NH₃ in MeOH in DCM 0/100 to 10/90), the desiredfractions were collected and concentrated in vacuo yielding the desiredproduct 89% pure. The compound was further purified by RP HPLC on C18XBridge™ (19×100 5 um). Mobile phase (Gradient from 80% 0.1%NH₄CO₃H/NH₄OH pH 9 solution in Water, 20% CH₃CN to 0% 0.1% NH₄CO₃H/NH₄OHpH 9 solution in Water, 100% CH₃CN), yielding E-4 (0.028 g, 21%) aswhite solid. M.P. >300° C. (Mettler FP 81HT/FP90).

Example 5 (E-5)3-(Cyclopropylmethyl)-N-[cis-4-(2,4-difluorophenyl)cyclohexyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-6)

Example E-5 was synthesized following the same approach described forE-1. Starting from I-20 (0.11 g, 0.41 mmol) and replacing intermediateI-33 for intermediate I-29, final product E-5 (0.088 g, 46.3%) wasobtained as white solid compound. M.P. 123.1° C. (Mettler FP 81HT/FP90).

Example 6 (E-6)3-(Cyclopropylmethyl)-N-(2,3-dihydro-1H-inden-2-yl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-6)

Example E-6 was synthesized following the same approach described forE-1. Starting from I-20 (0.11 g, 0.41 mmol) and replacing intermediateI-33 for 2-Aminoindane [(C.A.S. 2975-41-9), 0.058 mL, 0.44 mmol] finalproduct E-6 (0.065 g, 45.4%) was obtained as off-white solid compound.M.P. >300° C. (Mettler FP 81HT/FP90).

Example 7 (E-7)3-(Cyclopropylmethyl)-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine(E-6)

Example E-7 was synthesized following the same approach described forE-1. Starting from I-20 (0.11 g, 0.41 mmol) andcis-4-Phenylcyclohexylamine [(C.A.S. 5992-23-4), 0.050 mg, 0.4 mmol]final product E-7 (0.050 g, 35.2%) was obtained as white solid compound.M.P. 212.8° C. (Mettler FP 81HT/FP90).

Example 8 (E-8)3-Ethyl-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-8)

Example E-8 was synthesized following the same approach described forE-4. Starting from I-21 (0.1 g, 0.33 mmol, 80% pure) andcis-4-Phenylcyclohexylamine (C.A.S. 5992-23-4) final product E-8 (0.012g, 9.2%) was obtained as yellow oil.

Example 9 (E-9)N-[Cis-4-(2,4-difluorophenyl)cyclohexyl]-3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine(E-9)

Example E-9 was synthesized following the same approach described forE-4. Starting from I-21 (0.1 g, 0.41 mmol) and I-29 final product E-9(0.003 g) was obtained as clear oil.

Example 10 (E-10)3-(Ethoxymethyl)-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine(E-10)

Example E-10 was synthesized following the same approach described forE-1, starting from I-22 (0.15 g, 0.55 mmol) andcis-4-Phenylcyclohexylamine (C.A.S. 5992-23-4). After the addition ofsodium triacetoxyborohydride the reaction was heated at 120° C. for 20min under microwave irradiation instead of r.t. as reported for thesynthesis of final product E-1. The desired compound E-10 (0.037 g,15.5%) was obtained as cream solid. M.P. 137.3° C. (Mettler FP81HT/FP90).

Example 11 (E-11)3-(Ethoxymethyl)-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine(E-10)

Example E-11 was synthesized following the same approach described forE-1, starting from I-22 (0.15 g, 0.55 mmol) andtrans-4-Phenylcyclohexylamine (C.A.S. 5769-10-8). After the addition ofsodium triacetoxyborohydride the reaction was heated at 120° C. for 20min under microwave irradiation instead of r.t. as reported for thesynthesis of final product E-1. The desired compound E-11 (0.042 g,20.1%) was obtained as white solid. M.P. 144.2° C. (Mettler FP81HT/FP90).

Example 12 (E-12)8-Chloro-3-(cyclopropylmethyl)-N-(cis-4-phenylcyclohexyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine(E-12)

Example E-12 was synthesized following the same approach described forE-1, starting from I-6 (0.1 g, 0.42 mmol) andcis-4-Phenylcyclohexylamine (C.A.S. 5992-23-4). The final product E-12(0.045 g, 26.8%) was obtained as white solid. M.P. 267.9° C. (Mettler FP62).

Example 13 (E-13)8-Chloro-3-(cyclopropylmethyl)-N-(trans-4-phenylcyclohexyl)-1,2,4-triazolo-[4,3-a]pyridine-7-methanamine(E-13)

Example E-13 was synthesized following the same approach described forE-1, starting from I-6 (0.1 g, 0.42 mmol) andtrans-4-Phenylcyclohexylamine (C.A.S. 5769-10-8). The final product E-13(0.108 g, 64.4%) was obtained as cream solid. M.P. 171.1° C. (Mettler FP62).

Example 27 (E-27)Trans-N-{[3-(Cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenylcyclopropanamine(E-27)

A solution of I-35 (113 mg, 0.30 mmol) in CH₃CN (2 ml) was added to astirred solution of trans-2-phenylcyclopropylamine hydrochloride([CAS1986-47-6], 60.359 mg, 0.36 mmol) and DIPEA (0.155 mL, 0.89 mmol)in CH₃CN (1 mL) in a sealed tube. The mixture was stirred at 90° C. for18 h. The mixture was treated with sat. NaHCO₃ and extracted with EtOAc.The organic layer was separated, dried (Na₂SO₄), filtered and evaporatedin vacuo. The crude product was purified by flash column chromatography(silica; EtOAc in CH₂Cl₂ 0/100 to 20/80). The desired fractions werecollected and concentrated in vacuo. The product was triturated withethyl ether/diisopropyl ether to yield crude E-27, which was purified byRP HPLC on (C18 XBridge 30×100 5 μm). Mobile phase (Gradient from 80%0.1% NH₄CO₃H/NH₄OH pH 9 solution in Water, 20% MeOH to 0% 0.1%NH₄CO₃H/NH₄OH pH 9 solution in Water, 100% MeOH), yielding 34.37 mg of acrude, which was purified by flash column chromatography (silica; 7Nsolution of NH₃ in MeOH in DCM 0/100 to 10/90). The desired fractionswere collected and concentrated in vacuo to yield final product E-27 (24mg, 21%) as a colourless oil.

Examples 25 (E-25), 28a (E-28a) and 28b (E-28b)

N-{[3-(Cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-methyl}-3,4-dihydro-2H-chromen-4-amine(E-25), (4*R)—N-{[3-(Cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine(E-28a) and (4*S)—N-{[3-(Cyclopropylmethyl)-8-(trifluoro-methyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine(E-28b)

wherein each of *R and *S denote stereochemical configuration where theabsolute stereochemistry is undetermined but the compound itself hasbeen isolated as a single stereoisomer and is enantiomerically pure.

Sodium triacetoxyborohydride ([CAS56553-60-7], 295.21 mg, 1.39 mmol) wasadded to a stirred solution of I-20 (150 mg, 0.56 mmol) and I-37(137.916 mg, 0.67 mmol) in DCE (5.5 mL). The mixture was stirred at 120°C. for 20 minutes under microwave irradiation. The residue was dilutedin DCM and washed with sat sol. of NaHCO₃. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was dissolved in CH₃OH (4.1 mL) then sodium borohydride (47.081mg, 1.9 mmol) was added. The mixture was stirred at RT for 2 h. Thesolvent was evaporated in vacuo and the crude was purified by flashchromatography (silica, EtOAc in DCM 0/100 to 100/0). The desiredfractions were collected and concentrated in vacuo. The product waspurified by flash column chromatography (silica; 7 N solution of NH₃ inMeOH in DCM 0/100 to 10/90). The desired fractions were collected andconcentrated in vacuo to yield final compound E-25 (88 mg, 37%) as acream solid. E-25 was further purified by chiral SFC on CHIRALPAK AD-H 5μm 250×20 mm; mobile phase: 0.3% isopropylamine, 60% CO₂, 40% mixture ofEtOH/iPrOH 50/50 v/v), yielding final compound E-28a (28 mg, 13%) andfinal compound E-28b (24 mg, 11%).

Example 29 (E-29) (2S,4S)—N-{[3-(Cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenyltetrahydro-2H-pyran-4-amine(E-29)

A solution of I-24 (0.15 g, 0.429 mmol) in CH₃CN (3 mL) was added to astirred solution of I-41b (0.101 g, 0.47 mmol), DIPEA (221.99 μL, 1.29mmol) and NaI (0.00644 g, 0.043 mmol) in CH₃CN (2 mL) in a sealed tube.The mixture was stirred at 90° C. for 18 h. The solvent was evaporatedand the residue was purified by flash chromatography (silica; 7 Msolution of NH₃ in MeOH in DCM 0/100 to 10/90). The desired fractionswere collected and the solvents evaporated in vacuo. The desired productwas triturated with DIPE to give E-26 (58.8 mg, 32%) as a cream solid.

Example 30 (E-30)(2R,4R)—N-{[3-(Cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenyltetrahydro-2H-pyran-4-amine

Example E-30 was synthesized following the same approach described forE-29, starting from I-24 (0.15 g, 0.43 mmol) and I-41a (0.101 g, 0.47mmol). The final product E-30 (50 mg, 27%) was obtained as a cream solid

Example 31 (E-31) Cis-N-{[3-(Cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-4-phenyltetrahydrofuran-3-amine(E-31)

A solution of I-24 (0.25 g, 0.72 mmol) in CH₃CN (3 mL) were added to astirred solution of I-45 (0.143 g, 0.79 mmol), DIPEA (370.0 μL, 2.15mmol) and Nat (0.011 g, 0.072 mmol) in CH₃CN (2 mL) in a sealed tubeunder nitrogen. The mixture was stirred at 90° C. for 18 h. The solventwas evaporated and the residue was purified twice by flashchromatography (silica; MeOH in DCM 0/100 to 5/95 and 7 M solution ofNH₃ in MeOH in DCM 0/100 to 10/90). The desired fractions were collectedand the solvents evaporated in vacuo to give a brown oil, which waspurified by RP HPLC on C18 XBridge 19×100 5 um; mobile phase: gradientfrom 80% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in H₂O, 20% CH₃CN to 0% 0.1%NH₄CO₃H/NH₄OH pH 9 solution in H₂O, 100% CH₃CN), yielding final productE-31 (55.33 mg, 18%) as a yellow oil.

Table 1 below lists additional compounds of Formula (I).

TABLE 1 Example compounds according to Formula (I). Co. Exp Stereo- no.no. R¹ R² - - - -(CR³R⁴)NH—L chem. 1 E1

- - - -CF₃

trans 2 E2

- - - -CF₃

3 E3

- - - -CF₃

trans 4 E4

- - - -CF₃

trans 5 E5

- - - -CF₃

cis 6 E6

- - - -CF₃

7 E7

- - - -CF₃

cis 8 E8

- - - -CF₃

cis 9 E9

- - - -CF₃

cis 10 E10

- - - -CF₃

cis 11 E11

- - - -CF₃

trans 12 E12

- - - -Cl

cis 13 E13

- - - -Cl

trans 14 E1/E3

- - - -CF₃

15 E1/E3

- - - -CF₃

16 E1/E3

- - - -CF₃

17 E1/E3

- - - -CF₃

18 E1/E3

- - - -CF₃

19 E1/E3

- - - -CF₃

20 E1/E3

- - - -CF₃

21 E1/E3

- - - -CF₃

22 E1/E3

- - - -CF₃

23 E1/E3

- - - -CF₃

24 E1/E3

- - - -CF₃

25 E25

- - - -CF₃

26 E1/E3

- - - -CF₃

27 E27

- - - -CF₃

trans 28a E28a

- - - -CF₃

*R 28b E28b

- - - -CF₃

*S 29 E29

- - - -CF₃

2S, 4S 30 E30

- - - -CF₃

2R, 4R 31 E31

- - - -CF₃

cis Additional compounds 15-16, 18-25, and stereoisomers, particularlyenantiomers where applicable, thereof, to those exemplified in theexperimental section, can be prepared by analogy to the above examples(Exp. no.). The stereochemical configuration for some compounds has beendesignated *R or *S when their absolute stereochemistry is undeterminedalthough the compound itself has been isolated as a single stereoisomerand is enantiomerically pure.

C. Analytical Part Melting Points

Values are peak values, and are obtained with experimental uncertaintiesthat are commonly associated with this analytical method. For a numberof compounds, melting points were determined in open capillary tubeseither on a Mettler FP62 or on a Mettler FP81HT-FP90 apparatus. Meltingpoints were measured with a temperature gradient of 10° C./min. Maximumtemperature was 300° C. The melting point was read from a digitaldisplay.

LCMS

For LCMS characterization of the compounds of the present invention, thefollowing methods were used.

General Procedure A (for Waters MS Instruments) (TOF, ZQ, SQD)

The HPLC measurement was performed using an HP 1100 (AgilentTechnologies) system comprising a pump (quaternary or binary) withdegasser, an autosampler, a column oven, a diode-array detector (DAD)and a column as specified in the respective methods below. Flow from thecolumn was split to the MS spectrometer. The MS detector was configuredwith either an electrospray ionization source or an ESCI dual ionizationsource (electrospray combined with atmospheric pressure chemicalionization). Nitrogen was used as the nebulizer gas. The sourcetemperature was maintained at 140° C. Data acquisition was performedwith MassLynx-Openlynx software.

General Procedure B (for Waters MS Instruments (Acquity-SQD))

The UPLC (Ultra Performance Liquid Chromatography) measurement wasperformed using an Acquity UPLC (Waters) system comprising a samplerorganizer, a binary pump with degasser, a four column's oven, adiode-array detector (DAD) and a column as specified in the respectivemethods below. Column flow was used without split to the MS detector.The MS detector was configured with an ESCI dual ionization source(electrospray combined with atmospheric pressure chemical ionization).Nitrogen was used as the nebulizer gas. The source temperature wasmaintained at 140° C. Data acquisition was performed withMassLynx-Openlynx software.

Method 1

In addition to the general procedure A: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μm, 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution +5% acetonitrile), 5% B (mixture of acetonitrile/methanol,1/1), kept 0.2 minutes, to 100% B in 3.0 minutes, kept till 3.15 minutesand equilibrated to initial conditions at 3.30 minutes until 5.0minutes. Injection volume 2 μl. Low-resolution mass spectra (singlequadrupole, SQD detector) were acquired by scanning from 100 to 1000 in0.1 second using an inter-channel delay of 0.08 second. The capillaryneedle voltage was 3 kV. The cone voltage was 20 V and 50 V for positiveionization mode and 30 V for negative ionization mode.

Method 2

In addition to the general procedure B: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetate solution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 3.8 minutes,to 5% A, 95% B in 4.6 minutes, kept till 5.0 minutes. Injection volume2.0 μl. Low-resolution mass spectra (single quadrupole, SQD detector)were acquired by scanning from 100 to 1000 in 0.1 seconds using aninter-channel delay of 0.08 second. The capillary needle voltage was 3kV. The cone voltage was 25 V for positive ionization mode and 30 V fornegative ionization mode.

Method 3

same gradient as method 2; column used: RRHD Eclipse Plus-C18 (1.8 μm,2.1×50 mm) from Agilent.

General Procedure C (for Acquity-UPLC QUATTRO)

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.Mass spectra were acquired by scanning from 100 to 1000 in 0.2 secondsusing an interscan delay of 0.1 seconds. The capillary needle voltagewas 3 kV and the source temperature was maintained at 130° C. on theQuattro (triple quadrupole mass spectrometer from Waters). Nitrogen wasused as the nebulizer gas. Data acquisition was performed withMassLynx-Openlynx software (Waters).

Method 4

In addition to the general procedure C: Reversed phase UPLC was carriedout on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid)Phenyl-Hexyl column (1.7 μm, 2.1×100 mm) with a flow rate of 0.343ml/min. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5%acetonitrile; mobile phase B: 100% acetonitrile) were employed to run agradient condition from 84.2% A and 15.8% B (hold for 0.49 minutes) to10.5% A and 89.5% B in 2.18 minutes, hold for 1.94 min and back to theinitial conditions in 0.73 min, hold for 0.73 minutes. An injectionvolume of 2 ml was used. Cone voltage was 20V for positive and negativeionization mode.

SFCMS

For SFCMS characterization of compounds of the present invention, thefollowing method was used:

General Procedure

The SFC measurement was performed using Analytical system from Bergerinstrument comprises a FCM-1200 dual pump fluid control module fordelivering carbon dioxide (CO2) and modifier, a CTC Analytics automaticliquid sampler, a TCM-20000 thermal control module for column heatingfrom room temperature to 80° C. An Agilent 1100 UV photodiode arraydetector equipped with a high-pressure flow cell standing up to 400 barswas used. Flow from the column was split to a MS spectrometer. The MSdetector was configured with an atmospheric pressure ionization source.The following ionization parameters for the Waters ZQ massspectrophotometer are: corona: 9 μa, source temp: 140° C., cone: 30 V,probe temp 450° C., extractor 3 V, desolvatation gas 400 L/hr, cone gas70 L/hr. Nitrogen was used as the nebulizer gas. Data acquisition wasperformed with a Waters-Micromass MassLynx-Openlynx data system.

Method

In addition to the general procedure: The chiral separation in SFC wascarried out on a CHIRALPAK AD DAICEL column (10 μm, 4.6×250 mm) with aflow rate of 3.0 ml/min at 35° C. The mobile phase is 60% CO₂, 20%EtOH+20% iPrOH (containing 0.3% iPrNH₂, in EtOH/iPrOH 1:1) in isocraticmode.

Optical Rotations

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with asodium lamp and reported as follows: [α]_(λ) ^(t° C.) (c (g/100 ml,solvent).

Optical rotation values for enantiomerically pure compounds are shown intable 2a.

The results of the analytical measurements are shown in tables 2a and2b.

TABLE 2a Physico-chemical data for some compounds, retention time(R_(t)) in min, [M + H]⁺ peak (protonated molecule), LCMS method and mp(melting point in ° C.). Co. Mp R_(t) LCMS No. (° C.) [MH⁺] (min) MethodOptical Rotation 1 110.1 465 3.27 2 n.d. 2 118.2 466 2.82 2 n.d. 3 157.4429 3.13 2 n.d. 4 >300 403 3.02 1 n.d. 5 123.1 465 3.57 2 n.d. 6 >300387 2.53 2 n.d. 7 212.8 429 3.44 2 n.d. 8 nd 403 3.15 1 n.d. 9 n.d. n.d.n.d. n.d. n.d. 10  137.3 433 3.38 2 n.d. 11  144.2 433 3.08 2 n.d. 12 267.9 395 3.04 2 n.d. 13  171.1 395 2.68 2 n.d. 27  n.d. 387 2.63 3 n.d.28a n.d. 403 2.84 4 −46.0° (589 nm, c 0.50 w/v %, DMF, 20° C.) 28b n.d.403 2.84 4 +46.0° (589 nm, c 0.50 w/v %, DMF, 20° C.) 29  95.8 431 2.753 +21.6° (589 nm, c 0.50 w/v %, DMF, 20° C.) 30  139.6 431 2.74 3 −11.2°(589 nm, c 0.50 w/v %, DMF, 20° C.) 31  n.d. 417 2.35 3 n.d. (nd = notdetermined).

TABLE 2b Analytical SFC data - R_(t) means retention time (in minutes),[M + H]⁺ means the protonated mass of the compound, method refers to themethod used for SFC/MS analysis of enantiomerically pure compounds.Isomer Elution Co. Nr. R_(t) [M + H]⁺ UV Area % Order 28a 2.27 403 100 A28b 3.49 403 100 B

Nuclear Magnetic Resonance (NMR)

For a number of compounds, ¹H NMR spectra were recorded either on aBruker DPX-400 or on a Bruker AV-500 spectrometer with standard pulsesequences, operating at 400 MHz and 500 MHz, respectively. Chemicalshifts (6) are reported in parts per million (ppm) downfield fromtetramethylsilane (TMS), which was used as internal standard.

Co. No. 1

¹H NMR (400 MHz, CDCl₃) δ ppm 0.28-0.41 (m, 2H), 0.56-0.70 (m, 2H),1.14-1.23 (m, 1H), 1.24-1.36 (m, 2H), 1.58 (br. s., 1H), 1.51 (qd,J=12.9, 2.8 Hz, 2H), 1.84-1.96 (m, 2H), 2.04-2.16 (m, 2H), 2.57 (tt,J=11.1, 3.8 Hz, 1H), 2.81 (tt, J=12.2, 3.3 Hz, 1H), 3.11 (d, J=6.7 Hz,2H), 4.07 (br. d, J=1.8 Hz, 2H), 6.71-6.84 (m, 2H), 7.14 (td, J=8.4, 6.5Hz, 1H), 7.34 (d, J=7.4 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H).

Co. No. 2

¹H NMR (500 MHz, CDCl₃) δ ppm 0.29-0.40 (m, 2H), 0.58-0.68 (m, 2H),1.14-1.23 (m, 1H), 1.54-1.69 (m, 3H), 1.98-2.06 (m, 2H), 2.62-2.74 (m,3H), 3.11 (d, J=6.6 Hz, 2H), 3.34 (m, J=12.7 Hz, 2H), 4.08 (br. d, J=1.4Hz, 2H), 6.74-6.84 (m, 2H), 6.87-6.94 (m, 1H), 7.36 (d, J=7.2 Hz, 1H),8.07 (d, J=7.2 Hz, 1H).

Co. No. 3

¹H NMR (500 MHz, CDCl₃) δ ppm 0.29-0.40 (m, 2H), 0.57-0.68 (m, 2H),1.14-1.23 (m, 1H), 1.23-1.34 (m, 2H), 1.52 (qd, J=13.0, 3.0 Hz, 2H),1.58 (br. s., 1H), 1.90-2.01 (m, 2H), 2.04-2.16 (m, 2H), 2.52 (tt,J=12.2, 3.4 Hz, 1H), 2.58 (tt, J=11.1, 3.9 Hz, 1H), 3.11 (d, J=6.6 Hz,2H), 4.08 (br. d, J=1.4 Hz, 2H), 7.15-7.23 (m, 3H), 7.27-7.31 (m, 2H),7.33 (d, J=7.2 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H).

Co. No. 4

¹H NMR (400 MHz, CDCl₃) δ ppm 1.21-1.36 (m, 2H), 1.46-1.55 (m, 2H), 1.49(t, J=7.5 Hz, 3H), 1.58 (br. s., 1H), 1.91-2.00 (m, 2H), 2.05-2.14 (m,2H), 2.45-2.65 (m, 2H), 3.13 (q, J=7.6 Hz, 2H), 4.08 (br. d, J=1.8 Hz,2H), 7.16-7.22 (m, 3H), 7.27-7.32 (m, 2H), 7.34 (d, J=7.2 Hz, 1H), 7.96(d, J=7.2 Hz, 1H).

Co. No. 5

¹H NMR (400 MHz, CDCl₃) δ ppm 0.28-0.41 (m, 2H), 0.56-0.70 (m, 2H),1.13-1.24 (m, 1H), 1.54-1.67 (m, 3H), 1.67-1.75 (m, 2H), 1.75-1.84 (m,2H), 1.84-1.94 (m, 2H), 2.85 (tt, J=11.4, 3.0 Hz, 1H), 2.97-3.03 (m,1H), 3.11 (d, J=6.7 Hz, 2H), 4.01 (br. d, J=1.8 Hz, 2H), 6.72-6.85 (m,2H), 7.19 (td, J=8.5, 6.6 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 8.08 (d,J=7.2 Hz, 1H).

Co. No. 6

¹H NMR (500 MHz, CDCl₃) δ ppm 0.28-0.39 (m, 2H), 0.55-0.68 (m, 2H),1.13-1.22 (m, 1H), 1.62 (br. s., 1H), 2.81 (dd, J=15.6, 5.8 Hz, 2H),3.10 (d, J=6.6 Hz, 2H), 3.21 (dd, J=15.6, 6.9 Hz, 2H), 3.68 (quin, J=6.4Hz, 1H), 4.08 (br. d, J=1.4 Hz, 2H), 7.12-7.24 (m, 4H), 7.31 (d, J=7.2Hz, 1H), 8.05 (d, J=7.2 Hz, 1H).

Co. No. 7

¹H NMR (500 MHz, CDCl₃) δ ppm 0.29-0.40 (m, 2H), 0.57-0.69 (m, 2H),1.14-1.23 (m, 1H), 1.34 (br. s., 1H), 1.64-1.75 (m, 4H), 1.77-1.91 (m,4H), 2.58 (s, 1H), 2.92-3.02 (m, 1H), 3.11 (d, J=6.6 Hz, 2H), 4.01 (br.d, J=1.4 Hz, 2H), 7.17-7.22 (m, 1H), 7.22-7.26 (m, 2H), 7.28-7.33 (m,2H), 7.34 (d, J=7.2 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H).

Co. No. 8

¹H NMR (400 MHz, CDCl₃) δ ppm 1.50 (t, J=7.6 Hz, 3H), 1.56 (br. s., 1H),1.62-1.75 (m, 4H), 1.76-1.90 (m, 4H), 2.52-2.65 (m, 1H), 2.93-3.00 (m,1H), 3.13 (q, J=7.6 Hz, 2H), 4.01 (br. d, J=1.8 Hz, 2H), 7.17-7.26 (m,3H), 7.28-7.33 (m, 2H), 7.35 (d, J=7.2 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H).

Co. No. 9

¹H NMR (500 MHz, CDCl₃) δ ppm 1.50 (t, J=7.7 Hz, 3H), 1.56 (br. s., 1H),1.60-1.67 (m, 2H), 1.67-1.74 (m, 2H), 1.76-1.91 (m, 4H), 2.85 (tt,J=11.6, 3.3 Hz, 1H), 2.97-3.02 (m, 1H), 3.12 (q, J=7.5 Hz, 2H), 4.01(br. d, J=1.4 Hz, 2H), 6.73-6.79 (m, 1H), 6.79-6.84 (m, 1H), 7.19 (td,J=8.5, 6.6 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H).

Co. No. 10

¹H NMR (400 MHz, CDCl₃) δ ppm 1.21 (t, J=6.9 Hz, 3H), 1.57 (br. s., 1H),1.63-1.75 (m, 4H), 1.77-1.91 (m, 4H), 2.54-2.64 (m, 1H), 2.95-3.01 (m,1H), 3.56 (q, J=7.0 Hz, 2H), 4.03 (br. d, J=1.8 Hz, 2H), 5.08 (s, 2H),7.17-7.22 (m, 1H), 7.22-7.26 (m, 2H), 7.28-7.34 (m, 2H), 7.39 (d, J=7.2Hz, 1H), 8.36 (d, J=7.2 Hz, 1H).

Co. No. 11

¹H NMR (400 MHz, CDCl₃) δ ppm 1.21 (t, J=7.1 Hz, 3H), 1.23-1.35 (m, 2H),1.57 (br. s, 1H), 1.52 (qd, J=12.7, 3.2 Hz, 2H), 1.91-2.00 (m, 2H),2.06-2.15 (m, 2H), 2.52 (tt, J=12.3, 3.4 Hz, 1H), 2.59 (tt, J=11.1, 3.7Hz, 1H), 3.55 (q, J=6.9 Hz, 2H), 4.09 (br. d, J=1.8 Hz, 2H), 5.08 (s,2H), 7.16-7.23 (m, 3H), 7.27-7.32 (m, 2H), 7.38 (d, J=7.2 Hz, 1H), 8.35(d, J=7.2 Hz, 1H).

Co. No. 12

¹H NMR (500 MHz, CDCl₃) δ ppm 0.29-0.39 (m, 2H), 0.56-0.68 (m, 2H),1.15-1.24 (m, 1H), 1.57 (br. s., 1H), 1.63-1.73 (m, 4H), 1.80-1.92 (m,4H), 2.53-2.64 (m, 1H), 2.91-2.98 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 4.00(s, 2H), 7.14 (d, J=7.2 Hz, 1H), 7.17-7.22 (m, 1H), 7.22-7.28 (m, 2H),7.28-7.34 (m, 2H), 7.90 (d, J=7.2 Hz, 1H).

Co. No. 13

¹H NMR (400 MHz, CDCl₃) δ ppm 0.27-0.41 (m, 2H), 0.56-0.69 (m, 2H),1.15-1.23 (m, 1H), 1.23-1.36 (m, 2H), 1.43-1.64 (m, 3H), 1.89-1.99 (m,2H), 2.07-2.16 (m, 2H), 2.46-2.60 (m, 2H), 3.09 (d, J=6.7 Hz, 2H), 4.06(s, 2H), 7.11 (d, J=7.2 Hz, 1H), 7.15-7.22 (m, 3H), 7.26-7.32 (m, 2H),7.89 (d, J=6.9 Hz, 1H).

D. Pharmacological Examples [³⁵S]GTPγS Binding Assay

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Theeffects of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), are shown in Table 3.

[³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein α subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can be determinedmGluR2 receptors are shown to be preferentially coupled to Gai-protein,a preferential coupling for this method, and hence it is widely used tostudy receptor activation of mGluR2 receptors both in recombinant celllines and in tissues. Here we describe the use of the [³⁵S]GTPγS bindingassay using membranes from cells transfected with the human mGluR2receptor and adapted from Schaffhauser et al. ((2003) MolecularPharmacology 4:798-810) for the detection of the positive allostericmodulation (PAM) properties of the compounds of this invention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 h. Cells were then collected by scraping in PBS and cellsuspension was centrifuged (10 min at 4000 RPM in benchtop centrifuge).Supernatant was discarded and pellet gently resuspended in 50 mMTris-HCl, pH 7.4 by mixing with a vortex and pipetting up and down. Thesuspension was centrifuged at 16,000 RPM (Sorvall RC-5C plus rotorSS-34) for 10 minutes and the supernatant discarded. The pellet washomogenized in 5 mM Tris-HCl, pH 7.4 using an ultra-turrax homogenizerand centrifuged again (18,000 RPM, 20 min, 4° C.). The final pellet wasresuspended in 50 mM Tris-HCl, pH 7.4 and stored at −80° C. inappropriate aliquots before use. Protein concentration was determined bythe Bradford method (Bio-Rad, USA) with bovine serum albumin asstandard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulatory activity of testcompounds was performed as follows. Test compounds and glutamate werediluted in assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt,pH 7.4, 100 mM NaCl, 3 mM MgCl₂ and 10 μM GDP. Human mGlu2receptor-containing membranes were thawed on ice and diluted in assaybuffer supplemented with 14 μg/ml saponin. Membranes were pre-incubatedwith compound alone or together with a predefined (˜EC₂₀) concentrationof glutamate (PAM assay) for 30 min at 30° C. After addition of[³⁵S]GTPγS (f.c. 0.1 nM), assay mixtures were shaken briefly and furtherincubated to allow [³⁵S]GTPγS incorporation on activation (30 minutes,30° C.). Final assay mixtures contained 7 μg of membrane protein in 10mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 10 μMGDP and 10 μg/ml saponin. Total reaction volume was 200 μl. Reactionswere terminated by rapid filtration through Unifilter-96 GF/B plates(Perkin Elmer, Mass., USA) using a 96-well filtermate universalharvester. Filters were washed 6 times with ice-cold 10 mM NaH₂PO₄/10 mMNa₂HPO₄, pH 7.4. Filters were then air-dried, and 40 μl of liquidscintillation cocktail (Microscint-O) was added to each well.Membrane-bound radioactivity was counted in a Microplate Scintillationand Luminescence Counter from Perkin Elmer.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention—obtained in the presence of EC₂₀ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM)—weregenerated using the Lexis software interface (developed at J&J). Datawere calculated as % of the control glutamate response, defined as themaximal response that is generated upon addition of glutamate alone.Sigmoid concentration-response curves plotting these percentages versusthe log concentration of the test compound were analyzed usingnon-linear regression analysis. The concentration producing half-maximaleffect is then calculated as EC₅₀. The pEC₅₀ values below werecalculated as the −log EC₅₀, when the EC₅₀ is expressed in M. E_(max) isdefined as relative maximal effect (i.e. maximal % effect relative tothe control glutamate response).

Table 3 below shows the pharmacological data obtained for compounds ofFormula (I).

TABLE 3 Pharmacological data for compounds according to the invention.GTPγS- GTPγS- hmGluR2 hmGluR2 Co. no. PAM pEC₅₀ PAM E_(max) 1 7.08 276 26.21 321 3 6.63 235 4 5.92 197 5 7.42 279 6 6.10 227 7 7.37 263 8 6.49228 9 6.68 209 10  6.77 242 11  n.c. 278 12  6.23 257 13  n.c. 243 27 6.06 267 28a 6.1 257 28b 6.24 285 29  n.c. 209 30  5.92 239 31  n.c. 201n.c. means that the pEC₅₀ could not be calculatedpEC₅₀ values were not calculated in cases where theconcentration-response curve did not reach a plateau level.

All compounds were tested in presence of mGluR2 agonist glutamate at apredetermined EC₂₀ concentration, to determine positive allostericmodulation. pEC₅₀ values were calculated from a concentration-responseexperiment of at least 8 concentrations. If more experiments wereperformed, the average pEC₅₀ value is reported and error deviation was<0.5.

E. Prophetic Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mgIn this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound of formula (I)

or a stereochemically isomeric form thereof, wherein R¹ is selected from the group consisting of C₁₋₆alkyl; (C₃₋₈cycloalkyl)C₁₋₃alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl; and C₁₋₃alkyl substituted with 1, 2 or 3 fluoro substituents; R² is selected from the group consisting of Cl, CF₃, —CN and cyclopropyl; R³ is selected from the group consisting of hydrogen, methyl and CF₃; R⁴ is selected from the group consisting of hydrogen and methyl; or R³ and R⁴ together with the carbon to which they are bound form a cyclopropyl ring; L is selected from the group consisting of (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L-h):

wherein m^(a), M^(b), and m^(c) are each independently selected from the group consisting of 0 and 1; m^(e) and m^(g) are each independently selected from the group consisting of 1 and 2; n^(a), n^(b), n^(c), n^(d), n^(e), n^(f), h^(g) and n^(h) are each independently selected from the group consisting of 0, 1 and 2; R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g) and R^(5h) are each independently selected from the group consisting of halo; C₁₋₃alkyl; C₁₋₃alkyl substituted with 1, 2 or 3 fluoro substituents; C₁₋₃alkyloxy; and C₁₋₃alkyloxy substituted with 1, 2 or 3 fluoro substituents; R^(6a) is selected from the group consisting of hydrogen; halo; C₁₋₃alkyl; C₁₋₃alkyl substituted with 1, 2 or 3 fluoro substituents; C₁₋₃alkyloxy; and C₁₋₃alkyloxy substituted with 1, 2 or 3 fluoro substituents; R^(6c) is selected from the group consisting of hydrogen; halo; C₁₋₃alkyl; C₁₋₃alkyl substituted with 1, 2 or 3 fluoro substituents; C₁₋₃alkyloxy; C₁₋₃alkyloxy substituted with 1, 2 or 3 fluoro substituents; and cyclopropyl; R^(7a), R^(8a), R^(7b) and R^(8b) are each independently selected from the group consisting of hydrogen; fluoro and methyl; or R^(7a) and R^(8a), and R^(7b) and R^(8b) together with the carbon to which they are attached form a cyclopropyl or a carbonyl group; wherein each halo is selected from the group consisting of fluoro, chloro, bromo and iodo; with the proviso that (L-c) is not bound to the triazolopyridine core through a carbon atom that is alpha to the oxygen atom; or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, or a stereoisomeric form thereof, wherein R¹ is selected from the group consisting of (cyclopropyl)methyl; ethyl; and (ethoxy)methyl.
 3. The compound according to claim 1 wherein R¹ is (cyclopropyl)methyl.
 4. The compound according to claim 1, wherein R² is CF₃ or Cl.
 5. The compound according to claim 1, wherein R³ and R⁴ are both hydrogen.
 6. The compound according to claim 1, wherein L is selected from

wherein R^(5a) is fluoro and n^(a) is selected from the group consisting of 0, 1 and 2; R^(5b) is fluoro and n^(b) is selected from the group consisting of 0, 1 and 2; each R^(6c) is independently selected from hydrogen and methyl. n^(d) is 0; m^(e) is selected from the group consisting of 1 and 2; and m^(g) is selected from 1 and
 2. 7. The compound according to claim 1, selected from the group consisting of 3-(cyclopropylmethyl)-N-[trans-4-(2,4-difluorophenyl)cyclohexyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(cyclopropylmethyl)-N-[1-(2,4-difluorophenyl)-4-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(cyclopropylmethyl)-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-ethyl-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(cyclopropylmethyl)-N-[cis-4-(2,4-difluorophenyl)cyclohexyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(cyclopropylmethyl)-N-(2,3-dihydro-1H-inden-2-yl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(cyclopropylmethyl)-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-ethyl-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, N-[cis-4-(2,4-difluorophenyl)cyclohexyl]-3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(ethoxymethyl)-N-(cis-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 3-(ethoxymethyl)-N-(trans-4-phenylcyclohexyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 8-chloro-3-(cyclopropylmethyl)-N-(cis-4-phenylcyclohexyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, 8-chloro-3-(cyclopropylmethyl)-N-(trans-4-phenylcyclohexyl)-1,2,4-triazolo[4,3-a]pyridine-7-methanamine, trans-N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenylcyclopropanamine, N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine, (4*R)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine, (4*S)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-3,4-dihydro-2H-chromen-4-amine, (2S,4S)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenyltetrahydro-2H-pyran-4-amine, (2R,4R)—N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-2-phenyltetrahydro-2H-pyran-4-amine, and cis-N-{[3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl}-4-phenyltetrahydrofuran-3-amine, or a stereoisomeric form, a pharmaceutically acceptable salt thereof.
 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
 9. (canceled)
 10. A method for the treatment of a patient having a central nervous system disorder selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia comprising adminsiterin a pharmaceutically acceptable amount of a compound of claim 1 to said patient.
 11. The method according to claim 10, wherein the psychotic disorders are selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder; the anxiety disorders are selected from the group of agoraphobia, generalized anxiety disorder (GAD), mixed anxiety and depression, obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia and other phobias; the personality disorders are selected from the group of obsessive-compulsive personality disorder and schizoid, schizotypal disorder; the substance abuse or substance-related disorders are selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alco-hol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal; the eating disorders are selected from the group of anorexia nervosa and bulimia nervosa; the mood disorders are selected from the group of bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, treatment resistant depression, bipolar depression, and substance-induced mood disorder; the epilepsy or convulsive disorders are selected from the group of generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, epilepsy partialis continua, and other forms of epilepsy; the cognitive disorder is selected from the group of delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, behavioral and psychological symptoms of dementia, substance-induced persisting dementia and mild cognitive impairment.
 12. The method according to claim 10 the treatment of a central nervous system disorder selected from the group of schizophrenia, behavioral and psychological symptoms of dementia, major depressive disorder, treatment resistant depression, bipolar depression, anxiety, depression, generalised anxiety disorder, post-traumatic stress disorder, bi-polar mania, epilepsy, attention-deficit/hyperactivity disorder, substance abuse and mixed anxiety and depression.
 13. The method of claim 10 wherein additionally administered simultaneous, separate or sequential an orthosteric agonist of mGluR2 in a therapeutically effect amount for use in the treatment of the patient.
 14. A process for preparing a pharmaceutical composition a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in claim
 1. 15. A pharmaceutical composition comprising (a) a therapeutically effective amount of a compound as defined claim 1; and (b) therapeutically effective amount of an mGluR2 orthosteric agonist. 